Publications by authors named "Yip Han Chin"

36 Publications

Effect of COVID-19 Pandemic on Influenza Vaccination Intention: A Meta-Analysis and Systematic Review.

Vaccines (Basel) 2022 Apr 13;10(4). Epub 2022 Apr 13.

Department of Neonatology, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore.

Poorer outcomes have been reported with COVID-19 and influenza coinfections. As the COVID-19 pandemic rages on, protection against influenza by vaccination is becoming increasingly important. This study examines how COVID-19 has influenced influenza vaccination intentions from a global perspective. A literature search was conducted on Embase, PubMed, and CNKI from 1 January 2019 to 31 December 2021 for articles reporting rates of influenza vaccination pre-COVID-19 (19/20 season), and intention and/or uptake of influenza vaccination post-COVID-19 (20/21 season). The changes in vaccination intention and reasons for changes were reported. Subgroup analyses were performed by region, gender, age, and occupation. Newcastle Ottawa Scale was used for quality assessment of the articles. Twenty-seven studies with 39,193 participants were included. Among 22 studies reporting intention to vaccinate in 20/21, there was increased intention to vaccinate (RR 1.50, 95% CI 1.32-1.69, < 0.001) regardless of age, gender, and occupation. The remaining five studies reporting vaccination intention and uptake in 20/21 showed a similar increase (RR 1.68, 95%CI 1.20-2.36). Important determinants include historical vaccine acceptance, and perception of influenza severity and vaccine safety. The COVID-19 pandemic has increased intention to vaccinate against influenza internationally. The pandemic could be a window of opportunity to promote influenza vaccination and decrease vaccine hesitancy.
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http://dx.doi.org/10.3390/vaccines10040606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026798PMC
April 2022

Prognostic Outcomes in Acute Myocardial Infarction Patients Without Standard Modifiable Risk Factors: A Multiethnic Study of 8,680 Asian Patients.

Front Cardiovasc Med 2022 29;9:869168. Epub 2022 Mar 29.

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

Background: An increasing proportion of patients with acute myocardial infarction (AMI) are presenting without standard modifiable risk factors (SMuRFs) of hypertension, hypercholesterolemia, diabetes, and smoking, but with an unexpectedly increased mortality. This study examined the SMuRF-less patients presenting with AMI in a multiethnic Asian population.

Methods: We recruited patients presenting with AMI from 2011 to 2021 and compared the prevalence, clinical characteristics, and outcomes of SMuRF-less and SMuRF patients. Multivariable analysis was used to compare the outcomes of 30-day cardiovascular mortality, all-cause mortality, readmission, cardiogenic shock, stroke, and heart failure. Kaplan-Meier curves were constructed for 30-day cardiovascular mortality, with stratification by ethnicity, gender and AMI type, and 10-year all-cause mortality.

Results: Standard modifiable risk factor-less patients, who made up 8.6% of 8,680 patients, were significantly younger with fewer comorbidities that include stroke and chronic kidney disease, but higher rates of ventricular arrhythmias and inotropic or invasive ventilation requirement. Multivariable analysis showed higher rates of cardiovascular mortality (HR 1.48, 95% CI: 1.09-1.86, = 0.048), cardiogenic shock (RR: 1.31, 95% CI: 1.09-1.52, = 0.015), and stroke (RR: 2.51, 95% CI: 1.67-3.34, = 0.030) among SMuRF-less patients. A 30-day cardiovascular mortality was raised in the SMuRF-less group, with similar trends in men, patients with ST-segment elevation myocardial infarction (STEMI), and the three Asian ethnicities. All-cause mortality remains increased in the SMuRF-less group for up to 5 years.

Conclusion: There is a significant proportion of patients with AMI without standard risk factors in Asia, who have worse short-term mortality. This calls for greater focus on the management of this unexpectedly high-risk subgroup of patients.
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http://dx.doi.org/10.3389/fcvm.2022.869168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001931PMC
March 2022

Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Multivessel Coronary Artery Disease: A One-Stage Meta-Analysis.

Front Cardiovasc Med 2022 25;9:822228. Epub 2022 Mar 25.

Department of Cardiology, National University Heart Centre, Singapore, Singapore.

Background And Aims: Data are emerging on 10-year mortality comparing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) with stenting for multivessel disease (MVD) without left main (LM) involvement. We conducted an updated two-stage meta-analysis using reconstructed individual patient data to compare long-term mortality between CABG and PCI for patients with MVD without significant LM coronary disease.

Methods: Medline and Embase databases were searched for articles comparing CABG with PCI for MVD. A two-stage meta-analysis was conducted using reconstructed patient level survival data for all-cause mortality with subgroups by SYNTAX score. The shared-frailty and stratified Cox models were fitted to compare survival endpoints.

Results: We screened 1,496 studies and included six randomized controlled trials with 7,181 patients. PCI was associated with greater 10-year all-cause mortality risk (HR: 1.282, CI: 1.118-1.469, < 0.001) compared with CABG. In patients with low SYNTAX score, 10-year all-cause mortality after PCI was comparable to CABG (HR: 1.102, 0.822-1.479, = 0.516). However, in patients with moderate to high SYNTAX score, 10-year all-cause mortality was significantly higher after PCI compared with CABG (HR: 1.444, 1.122-1.858, < 0.001; HR: 1.856, 1.380-2.497, < 0.001, respectively).

Conclusion: This updated reconstructed individual patient-data meta-analysis revealed a sustained lower cumulative all-cause mortality of CABG over PCI for multivessel disease without LM involvement.
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http://dx.doi.org/10.3389/fcvm.2022.822228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990308PMC
March 2022

Meta-Analysis of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Narrowing.

Am J Cardiol 2022 Apr 4. Epub 2022 Apr 4.

Department of Cardiology, National University Heart Centre, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Randomized controlled trials (RCTs) comparing percutaneous coronary intervention (PCI) with drug-eluting stents and coronary artery bypass grafting (CABG) for patients with left main coronary artery disease (LMCAD) have reported conflicting results. We performed a systematic review up to May 23, 2021, and 1-stage reconstructed individual patient data meta-analysis (IPDMA) to compare outcomes between both groups. The primary outcome was 10-year all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, and unplanned revascularization at 5 years. We performed individual patient data meta-analysis using published Kaplan-Meier curves to provide individual data points in coordinates and numbers at risk were used to increase the calibration accuracy of the reconstructed data. Shared frailty model or, when proportionality assumptions were not met, a restricted mean survival time model were fitted to compare outcomes between treatment groups. Of 583 articles retrieved, 5 RCTs were included. A total of 4,595 patients from these 5 RCTs were randomly assigned to PCI (n = 2,297) or CABG (n = 2,298). The cumulative 10-year all-cause mortality after PCI and CABG was 12.0% versus 10.6%, respectively (hazard ratio [HR] 1.093, 95% confidence interval [CI] 0.925 to 1.292; p = 0.296). PCI conferred similar time-to-MI (restricted mean survival time ratio 1.006, 95% CI 0.992 to 1.021, p=0.391) and stroke (restricted mean survival time ratio 1.005, 95% CI 0.998 to 1.013, p = 0.133) at 5 years. Unplanned revascularization was more frequent after PCI than CABG (HR 1.807, 95% CI 1.524 to 2.144, p <0.001) at 5 years. This meta-analysis using reconstructed participant-level time-to-event data showed no statistically significant difference in cumulative 10-year all-cause mortality between PCI versus CABG in the treatment of LMCAD.
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http://dx.doi.org/10.1016/j.amjcard.2022.02.044DOI Listing
April 2022

Metabolic Associated Fatty Liver Disease Increases the Risk of Systemic Complications and Mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals.

Endocr Pract 2022 Mar 29. Epub 2022 Mar 29.

Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore. Electronic address:

Objective: The recent introduction of the term metabolic associated fatty liver disease (MAFLD) sought to reclassify nonalcoholic fatty liver disease (NAFLD). MAFLD is thought to improve the encapsulation of metabolic dysregulation. However, recent evidence has found significant differences between MAFLD and NAFLD, and prevailing knowledge has largely arisen from studies on NAFLD. Hence, we conducted a meta-analysis and systematic review of the outcomes associated with MAFLD.

Methods: MEDLINE and Embase databases were searched for articles relating to outcomes in MAFLD. Analysis was conducted in random effects with hazard ratios (HRs) to account for longitudinal risk assessment of mortality and systemic complications.

Results: A total of 554 articles were identified, of which 17 articles were included. MAFLD resulted in an increase in the overall mortality (HR, 1.24; confidence interval [CI], 1.13-1.34), cancer-related mortality (HR, 1.27; CI, 1.01-1.54), and cardiovascular disease mortality (HR, 1.28, 1.03-1.53; P = .04) compared with non-MAFLD. MAFLD also increases the risk of cardiovascular events (HR, 1.49; CI, 1.34-1.64; P < .01), stroke (HR, 1.55; CI, 1.37-1.73; P < .01), and chronic kidney disease (HR, 1.53; CI, 1.38-1.68). The presence of MAFLD was also associated with an increased risk of heart failure, obstructive sleep apnea, and malignancy.

Conclusion: MAFLD can significantly elevate the risk of systemic diseases and mortality. The care of MAFLD thus requires interdisciplinary collaboration, and future clinical trials conducted on MAFLD should aim to reduce the incidence of end-organ damage aside from improving liver histology.
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http://dx.doi.org/10.1016/j.eprac.2022.03.016DOI Listing
March 2022

Non-alcoholic fatty liver disease association with structural heart, systolic and diastolic dysfunction: a meta-analysis.

Hepatol Int 2022 Apr 23;16(2):269-281. Epub 2022 Mar 23.

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

Objective: Several studies have documented a relationship between non-alcoholic fatty liver disease (NAFLD) and structural heart disease, particularly diastolic function. This meta-analysis will be the first to examine the echocardiographic-derived cardiac function and structural characteristics in NAFLD patients, and its association with liver disease severity and metabolic profile.

Methods: Medline and Embase were searched and pairwise meta-analysis was conducted in DerSimonian and Laird to obtain the odds ratio (OR) and mean difference (MD) for dichotomous and continuous variables, respectively, to compare the effects of NAFLD on the echocardiography parameters.

Results: Forty-one articles involving 33,891 patients underwent echocardiography. NAFLD patients had worse systolic indices with lower ejection fraction (EF, MD: - 0.693; 95% CI: - 1.112 to - 0.274; p = 0.001), and worse diastolic indices with higher E/e' (MD: 1.575; 95% CI: 0.924 to 2.227; p < 0.001) compared to non-NAFLD patients. NAFLD patients displayed increased left ventricular mass (LVM, MD: 34.484; 95% CI: 26.236 to 42.732; p < 0.001) and epicardial adipose thickness (EAT, MD: 0.1343; 95% CI: 0.055 to 0.214; p = 0.001). An increased severity of NAFLD was associated with worse diastolic indices (decreased E/A ratio, p = 0.007), but not with systolic indices.

Conclusions: NAFLD is associated with impaired systolic and diastolic function with changes in cardiac structure. Concomitant metabolic risk factors and liver disease severity are independently associated with worsening systolic and diastolic function.
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http://dx.doi.org/10.1007/s12072-022-10319-6DOI Listing
April 2022

Long-Term Prognosis in Patients with Concomitant Acute Coronary Syndrome and Aortic Stenosis.

Can J Cardiol 2022 Mar 18. Epub 2022 Mar 18.

Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore; Department of Medicine, National University Hospital, Singapore.

Background: Aortic stenosis (AS) and acute coronary syndrome (ACS) share similar cardiovascular risk factors. The incidence of concomitant AS and ACS is increasing with aging population, yet studies investigating the prognosis of these patients remain scarce.

Methods: This retrospective single-centre cohort study examined consecutive patients presented with ACS and AS between 1 January 2011 and 31 March 2021. The cohort was divided into mild, moderate and severe AS based on index echocardiogram. The primary outcome was all-cause mortality.

Results: Of 563 patients, 264 had mild (46.9%), 193 moderate (34.3%) and 106 severe AS (18.8%). The mean follow-up duration was 2.5 years. All-cause mortality was higher among patients with moderate and severe AS compared to mild AS within 30-days (17.0% vs. 13.0% vs. 6.4%, p=0.005) and in the long-term (49.7% vs. 51.4% vs. 35.6% respectively, p=0.002). Concomitant moderate (HR 1.453, 95% CI 1.020-2.068, p=0.038) or severe AS (HR 1.873, 95% CI 1.176-2.982, p=0.008) were independent predictors of all-cause mortality. Kaplan-Meier curves demonstrated higher mortality in patients with moderate and severe AS compared to mild AS (p<0.001). Similar survival trends were observed regardless of ACS type and in those with preserved LVEF. Patients with reduced left ventricular ejection fraction had poor prognosis regardless of AS severity.

Conclusions: ACS patients with concomitant moderate or severe AS have comparable high long-term mortality, regardless of the ACS type. The high early mortality in moderate and severe AS emphasizes the imperative to attempt to mitigate this risk urgently.
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http://dx.doi.org/10.1016/j.cjca.2022.03.010DOI Listing
March 2022

Meta-analysis: analysis of mechanistic pathways in the treatment of non-alcoholic steatohepatitis. Evidence from a Bayesian network meta-analysis.

Aliment Pharmacol Ther 2022 May 14;55(9):1076-1087. Epub 2022 Mar 14.

Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA.

Background And Aims: Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease. However, there is lack of comparison of efficacy between different NASH drug classes. We conducted a network meta-analysis evaluating drug classes through comparing histological outcomes and targets of drugs.

Approach And Results: Medline, EMBASE and CENTRAL were searched for randomised controlled trials evaluating NASH drugs in biopsy-proven NASH patients. Primary outcomes included NASH resolution without worsening of fibrosis, at least 2-point reduction in Non-alcoholic fatty liver disease Activity Score (NAS) without worsening of fibrosis and at least 1-point reduction in fibrosis. Treatments were classified into inflammation, energy, bile acid and fibrosis modulators. The analysis was conducted with Bayesian network model and surface under the cumulative ranking curve (SUCRA) analysis. Among 49 included trials, treatments modulating energy (Risk ratio (RR): 1.92, Credible intervals (Crl): 1.59-2.34) were most likely to achieve NASH resolution followed by treatments modulating fibrosis (RR 1.66, Crl: 0.65-4.50), bile acids (RR: 1.37, Crl: 0.99-1.92) and inflammation (RR: 1.00, Crl: 0.75-1.33). Energy and bile acids modulation were effective in at least 2-point NAS reduction without worsening of fibrosis (RR: 1.52, Crl 1.30-1.77; RR: 1.69, Crl 1.41-2.03) and at least 1-point reduction in fibrosis (RR: 1.26, Crl:1.05-1.49; RR: 1.54, Crl: 1.20-1.97).

Conclusions: This network analysis demonstrates the relative superiority of drugs modulating energy pathways and bile acids in NASH treatment. This guides the development and selection of drugs for combination therapies.
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http://dx.doi.org/10.1111/apt.16808DOI Listing
May 2022

Meta-Analysis Comparing Risk Factors, Incidence, and Outcomes of Patients With Versus Without Prosthesis-Patient Mismatch Following Transcatheter Aortic Valve Implantation.

Am J Cardiol 2022 May 19;170:91-99. Epub 2022 Feb 19.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Cardiology, National University Heart Centre, Singapore.

Current guidelines on the management of patients with aortic valvular disease have widened the use of transcatheter aortic valve implantation (TAVI) with an emphasis on avoidance of prosthesis-patient mismatch (PPM). This study sought to examine the incidence, risk factors, and all-cause mortality of PPM after TAVI. Medline and Embase databases were searched from inception to August 10, 2021. Patients were compared along 2 arms: (1) any degree of PPM and those without PPM, (2) severe PPM, and nonsevere PPM. A total of 22 articles involving 115,442 patients after TAVI were included. Pooled incidence for any degree of PPM was 30.1% and 10.7% in severe PPM. Incidence was significantly higher (p <0.001) for any degree of PPM in Europe (33.1%) and North America (34.4%) compared with Asia (10.4%). Incidence of severe PPM was higher (p = 0.015) in older generation (13.6%) compared with current-generation valves (6.3%). Severe PPM increased the risk of all-cause mortality relative to nonsevere PPM (hazard ratio: 1.86, 95% confidence interval: 1.05 to 3.29, p = 0.034). Patients of younger age, increased body surface area, lower left ventricular ejection fraction, and classified New York Heart Association Class III/IV were at greater risk of both any degree and severe PPM. Smaller prosthesis size increased the risk of any degree of PPM, whereas postdilation and larger prostheses were protective factors. In conclusion, all-cause mortality was significantly affected in severe PPM compared with nonsevere cases, whereas this excess mortality was not observed between those with any degree of PPM and those without. Closer attention to patient and bioprosthetic valve factors is required to minimize the occurrence of severe PPM.
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http://dx.doi.org/10.1016/j.amjcard.2022.01.023DOI Listing
May 2022

Clinical, echocardiographic and prognostic outcomes of patients with concordant and discordant high-gradient aortic stenosis in an Asian cohort.

Int J Cardiovasc Imaging 2022 Feb 19. Epub 2022 Feb 19.

Department of Cardiology, National University Heart Centre Singapore, National University Hospital, 1E Kent Ridge Road, Singapore, 119228, Singapore.

Literature of patients with severe high-gradient aortic stenosis (HG AS) (mean pressure gradient [MPG] ≥ 40 mmHg and aortic valve area [AVA] ≥ 1.0 cm) remains limited. This study seeks to compare the prognostic outcomes of patients with high-gradient concordant (HGAS) and discordant AS (HGAS) in an Asian cohort. From 2010 to 2015, patients with moderate-to-severe AS with preserved left ventricular ejection fraction (LVEF ≥ 50%) were recruited and stratified into 3 groups based on index echocardiogram-(1) HGAS, (2) HGAS and (3) moderate AS (M-AS). The primary study endpoints was all-cause mortality, with secondary endpoints of congestive heart failure (CHF) admissions and aortic valve replacement (AVR). Multivariable Cox regression was used and Kaplan-Meier curves were constructed to evaluate associations between HG-AS, HG-AS and M-AS, and the study outcomes. A total of 467 patients were studied, comprising of 6.2% HGAS, 13.9% HG-AS and 79.9% M-AS patients. There was significantly higher AVR rates in the HG-AS group (58.5%), followed by HG-AS (31.0%) and M-AS (4.6%), p < 0.001) groups. After adjusting for confounders, HG-AS was significantly associated with all-cause mortality (HR 3.082, 95% CI 1.479-6.420, p = 0.003) and CHF admissions (HR 12.728, 95% CI 2.922-55.440 p = 0.001) but not HG-AS, with M-AS as the reference group. Both HG-AS (HR 7.715, 95% CI 2.927-20.338; p < 0.001) and HG-AS (HR 21.960, 95% CI 10.833-44.515, p < 0.001) were independent predictors of AVR. After exclusion of reversible high-flow states, HG-AS patients appear to have a more favourable prognostic profile compared to HG-AS patients. Large prospective interventional studies examining the prognostic differences between the two groups will be the next important step.
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http://dx.doi.org/10.1007/s10554-022-02524-zDOI Listing
February 2022

Can glucose-lowering medications improve outcomes in non-diabetic heart failure patients? A Bayesian network meta-analysis.

ESC Heart Fail 2022 04 29;9(2):1338-1350. Epub 2022 Jan 29.

Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, 117597, Singapore.

Aims: The cardioprotective effects of glucose-lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose-lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta-analysis to evaluate the impact of various glucose-lowering medications on the outcomes of non-diabetic HF patients.

Methods And Results: Medline and Embase were searched for RCTs investigating the use of glucose-lowering medications in non-diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre-defined datasheet. Primary outcomes include serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO ). A Bayesian network meta-analysis was performed to compare the effectiveness of different classes of glucose-lowering medications in improving HF outcomes. Risk-of-bias was assessed using Cochrane Risk-of-Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium-glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT-proBNP, with the significant reduction in NT-proBNP when compared with glucagon-like peptide-1 receptor agonists (GLP1-RA) [mean differences (MD): -229.59 pg/mL, 95%-credible intervals (95%-CrI): -238.31 to -220.91], metformin (MD: -237.15 pg/mL, 95%-CrI: -256.19 to -218.14), and placebo (MD: -228.00 pg/mL, 95%-CrI: -233.99 to -221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1-RA (MD: 8.09%, 95%-CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%-CrI: 4.37 to 7.84). SGLT2i and GLP1-RA were more favourable to placebo in improving PVO , with significant increase of PVO at a MD of 1.60 mL/kg/min (95%-CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%-CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo.

Conclusions: This Bayesian network meta-analysis demonstrated that SGLT2i, when compared with GLP1-RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO and NT-proBNP in non-diabetic HF patients. Further large-scale prospective studies are needed to confirm these preliminary findings.
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http://dx.doi.org/10.1002/ehf2.13822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934935PMC
April 2022

Placebo effect on progression and regression in NASH: Evidence from a meta-analysis.

Hepatology 2022 Jun 24;75(6):1647-1661. Epub 2022 Jan 24.

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

Background And Aims: The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH.

Methods: A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences.

Results: This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients.

Conclusions: Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
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http://dx.doi.org/10.1002/hep.32315DOI Listing
June 2022

Comparison of biodegradable and newer generation durable polymer drug-eluting stents with short-term dual antiplatelet therapy: a systematic review and Bayesian network meta-analysis of randomized trials comprising of 43,875 patients.

J Thromb Thrombolysis 2022 Apr 4;53(3):671-682. Epub 2022 Jan 4.

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

Newer generation durable polymer drug-eluting stents (DP-DES) and biodegradable polymer DES (BP-DES) have similar efficacy with dual-antiplatelet therapy (DAPT) duration of > 6 months. However, this difference in outcomes have not been well studied in shorter DAPT regime. This study compares the safety and efficacy profiles of DP-DES and BP-DES based on short-term (1-3 months), intermediate-term (4-6 months) and standard DAPT (6-12 months) durations. A search was conducted on Embase and Medline for Randomized Controlled Trials (RCTs) comparing stent types, and DAPT durations. Primary endpoints include cardiac death, myocardial infarction (MI), definite stent thrombosis, stroke, target vessel revascularization (TVR) and major bleeding. Network analysis was conducted to summarize the evidence. A total of 15 RCTs involving 43,875 patients were included. DP-DES was associated with significantly lower major bleeding rates compared to BP-DES (RR 0.44, Crl 0.22-0.83) in short-term DAPT. Among DP-DES patients, short-term DAPT was associated with lower major bleeding risk compared to standard DAPT (RR 0.47, CrI 0.32-0.69). This favorable bleeding profile with short DAPT was not found in BP-DES patients. Cardiac death, MI, definite stent thrombosis, stroke and TVR rates were similar across the various DAPT durations and stent types. Our preliminary findings demonstrated comparable efficacy and safety outcomes between BP-DES and newer generation BP-DES across various DAPT durations. In patients requiring short DAPT, DP-DES had more favourable major bleeding profile compared to BP-DES, without compromising anti-thrombotic efficacy.
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http://dx.doi.org/10.1007/s11239-021-02628-8DOI Listing
April 2022

Long-term outcomes after out-of-hospital cardiac arrest: A systematic review and meta-analysis.

Resuscitation 2022 02 29;171:15-29. Epub 2021 Dec 29.

Department of Emergency Medicine, Singapore General Hospital, Singapore; Saw Swee Hock School of Public Health, National University Singapore, Singapore; Pre-hospital and Emergency Research Centre, Duke-NUS Medical School, Singapore. Electronic address:

Aims: Long term outcomes after out-of-hospital cardiac arrest (OHCA) are not well understood. This study aimed to evaluate the long-term (1-year and beyond) survival outcomes, including overall survival and survival with favorable neurological status and the quality-of-life (QOL) outcomes, among patients who survived the initial OHCA event (30 days or till hospital discharge).

Methods: Embase, Medline and PubMed were searched for primary studies (randomized controlled trials, cohort and cross-sectional studies) which reported the long-term survival outcomes of OHCA patients. Data abstraction and quality assessment was conducted, and survival at predetermined timepoints were assessed via single-arm meta-analyses of proportions, using generalized linear mixed models. Comparative meta-analyses were conducted using the Mantel-Haenszel Risk Ratio (RR) estimates, using the DerSimonian and Laird model.

Results: 67 studies were included, and among patients that survived to hospital discharge or 30-days, 77.3% (CI = 71.2-82.4), 69.6% (CI = 54.5-70.3), 62.7% (CI = 54.5-70.3), 46.5% (CI = 32.0-61.6), and 20.8% (CI = 7.8-44.9) survived to 1-, 3-, 5-, 10- and 15-years respectively. Compared to Asia, the probability of 1-year survival was greater in Europe (RR = 2.1, CI = 1.8-2.3), North America (RR = 2.0, CI = 1.7-2.2) and Oceania (RR = 1.9, CI = 1.6-2.1). Males had a higher 1-year survival (RR:1.41, CI = 1.25-1.59), and patients with initial shockable rhythm had improved 1-year (RR = 3.07, CI = 1.78-5.30) and 3-year survival (RR = 1.45, CI = 1.19-1.77). OHCA occurring in residential locations had worse 1-year survival (RR = 0.42, CI = 0.25-0.73).

Conclusion: Our study found that up to 20.8% of OHCA patients survived to 15-years, and survival was lower in Asia compared to the other regions. Further analysis on the differences in survival between the regions are needed to direct future long-term treatment of OHCA patients.
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http://dx.doi.org/10.1016/j.resuscitation.2021.12.026DOI Listing
February 2022

An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD.

Clin Gastroenterol Hepatol 2021 Dec 4. Epub 2021 Dec 4.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore. Electronic address:

Background & Aims: The shift to redefine nonalcoholic fatty liver disease (NAFLD) as metabolic associated fatty liver disease (MAFLD) can profoundly affect patient care, health care professionals, and progress within the field. To date, there remains no consensus on the characterization of NAFLD vs MAFLD. Thus, this study sought to compare the differences between the natural history of NAFLD and MAFLD.

Methods: Medline and Embase databases were searched to include articles on prevalence, risk factors, or outcomes of patients with MAFLD or NAFLD. Meta-analysis of proportions was conducted using the generalized linear mix model. Risk factors and outcomes were evaluated in conventional pairwise meta-analysis.

Results: Twenty-two articles involving 379,801 patients were included. Pooled prevalence of MAFLD was 39.22% (95% confidence interval [CI], 30.96%-48.15%) with the highest prevalence in Europe and Asia, followed by North America. The current MAFLD Definition only accounted for 81.59% (95% CI, 66.51%-90.82%) of NAFLD diagnoses. Patients had increased odds of being diagnosed with MAFLD compared with NAFLD (odds ratio, 1.37; 95% CI, 1.16-1.63; P < .001). Imaging modality resulted in a significantly higher odds of being diagnosed with MAFLD compared with NAFLD, but not biopsy. MAFLD was significantly associated with males, higher body mass index, hypertension, diabetes, lipids, transaminitis, and greater fibrosis scores compared with NAFLD.

Conclusions: There were stark differences in the prevalence and risk factors between MAFLD and NAFLD. However, in the use of the MAFLD Definition, a greater emphasis on the management of concomitant metabolic diseases and a collaborative effort is required to explore the complex pathophysiologic mechanisms underlying the disease.
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http://dx.doi.org/10.1016/j.cgh.2021.11.038DOI Listing
December 2021

Development and validation of the SARICA score to predict survival after return of spontaneous circulation in out of hospital cardiac arrest using an interpretable machine learning framework.

Resuscitation 2022 01 26;170:126-133. Epub 2021 Nov 26.

Pre-hospital and Emergency Research Centre, Duke-NUS Medical School, Singapore; Department of Emergency Medicine, Singapore General Hospital, Singapore. Electronic address:

Background: Accurate and timely prognostication of patients with out-of-hospital cardiac arrest (OHCA) who achieved the return of spontaneous circulation (ROSC) is crucial in clinical decision-making, resource allocation, and communications with next-of-kins. We aimed to develop the Survival After ROSC in Cardiac Arrest (SARICA), a practical clinical decision tool to predict survival in OHCA patients who attained ROSC.

Methods: We utilized real-world Singapore data from the population-based Pan-Asian Resuscitation Outcomes Study between 2010-2018. We excluded patients without ROSC. The dataset was segmented into training (60%), validation (20%) and testing (20%) cohorts. The primary endpoint was survival (to 30-days or hospital discharge). AutoScore, an interpretable machine-learning based clinical score generation algorithm, was used to develop SARICA. Candidate factors were chosen based on objective demographic and clinical factors commonly available at the time of admission. Performance of SARICA was evaluated based on receiver-operating curve (ROC) analyses.

Results: 5970 patients were included, of which 855 (14.3%) survived. A three-variable model was determined to be most parsimonious. Prehospital ROSC, age, and initial heart rhythm were identified for inclusion via random forest selection. Finally, SARICA consisted of these 3 variables and ranged from 0 to 10 points, achieving an area under the ROC (AUC) of 0.87 (95% confidence interval: 0.84-0.90) within the testing cohort.

Conclusion: We developed and internally validated the SARICA score to accurately predict survival of OHCA patients with ROSC at the time of admission. SARICA is clinically practical and developed using an interpretable machine-learning framework. SARICA has unknown generalizability pending external validation studies.
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http://dx.doi.org/10.1016/j.resuscitation.2021.11.029DOI Listing
January 2022

The Association of Plant-Based Diet With Cardiovascular Disease and Mortality: A Meta-Analysis and Systematic Review of Prospect Cohort Studies.

Front Cardiovasc Med 2021 5;8:756810. Epub 2021 Nov 5.

Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore.

The association between plant-based diets and cardiovascular disease (CVD) remains poorly characterized. Given that diet represents an important and a modifiable risk factor, this study aimed to assess (1) the relationships between the impact of adherence to plant-based diets on cardiovascular mortality, incident CVD, and stroke; (2) if associations differed by adherence to healthful and less healthful plant-based diets. MEDLINE and EMBASE databases were searched up to May 2021. Studies assessing CVD outcomes with relation to plant-based dietary patterns or according to plant-based dietary indices (PDI) were included. A meta-analysis of hazard ratios (HR) was conducted using DerSimonian and Laird random effects model. Thirteen studies involving 410,085 participants were included. Greater adherence to an overall plant-based dietary pattern was significantly associated with a lower risk of cardiovascular mortality (pooled HR: 0.92, 95% CI: 0.86-0.99 = 0.0193, = 88.5%, = 124,501) and a lower risk of CVD incidence (pooled HR: 0.90, 95% CI: 0.82-0.98, = 0.0173, = 87.2%, = 323,854). Among the studies that used PDI, unhealthful plant-based diets were associated with increased risk of cardiovascular mortality (pooled HR: 1.05, 95% CI: 1.01-1.09, = 0.0123, = 0.00%, = 18,966), but not CVD incidence. Conversely, healthful plant-based diets were associated with decreased CVD incidence (pooled HR: 0.87, 95% CI: 0.80-0.95, = 0.0011, = 57.5%, = 71,301), but not mortality. Vegetarians also had significantly lower CVD incidence (HR: 0.81, 95% CI: 0.72-0.91, = 0.0004, = 22.2%, = 16,254), but similar CVD mortality or stroke risk when compared to the meat-eaters. To date, this comprehensive study examines the effects of a plant-based diet on major clinical endpoints using more holistic PDIs. These findings highlight the favorable role of healthful plant-based foods in reducing cardiovascular mortality and CVD.
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http://dx.doi.org/10.3389/fcvm.2021.756810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604150PMC
November 2021

Laparoscopic versus open resection for rectal cancer: An individual patient data meta analysis of randomized controlled trials.

Eur J Surg Oncol 2022 May 11;48(5):1133-1143. Epub 2021 Nov 11.

Yong Loo Lin School of Medicine, National University Singapore, Singapore; Division of Colorectal Surgery, Department of Surgery, National University Hospital, Singapore. Electronic address:

Background And Aims: The role of laparoscopic rectal cancer resection remains controversial. Thus, we aimed to conduct a one-stage meta-analysis with reconstructed patient-level data using randomized trial data to compare long-term oncologic efficacy of laparoscopic and open surgical resection for rectal cancer.

Methods: Medline, EMBASE and Scopus were searched for articles comparing laparoscopic with open surgery for rectal cancer. Primary outcome was disease free survival (DFS) while secondary outcome was overall survival (OS). One-stage meta-analysis was conducted using patient-level survival data reconstructed from Kaplan-Meier curves with Web Plot Digitizer. Shared-frailty and stratified Cox models were fitted to compare survival endpoints.

Results: Seven randomized trials involving 1767 laparoscopic and 1293 open resections for rectal cancer were included. There were no significant differences between both groups for DFS and OS with respective hazard ratio estimates of 0.91 (95% CI: 0.78-1.06, p = 0.241) and 0.86 (95% CI:0.73-1.02, p = 0.090). Sensitivity analysis for non-metastatic patients and patients with mid and lower rectal cancer showed no significant differences in OS and DFS between both surgical approaches. In the laparoscopic arm, improved DFS was noted for stage II (HR: 0.73, 95% CI:0.54-0.98, p = 0.036) and stage III rectal cancers (HR: 0.74, 95% CI:0.55-0.99, p = 0.041).

Conclusions: This meta-analysis concludes that laparoscopic rectal cancer resection does not compromise long-term oncologic outcomes compared with open surgery with potential survival benefits for a minimal access approach in patients with stage II and III rectal cancer.
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http://dx.doi.org/10.1016/j.ejso.2021.11.012DOI Listing
May 2022

Small bowel adenocarcinoma in Crohn's disease: a systematic review and meta-analysis of the prevalence, manifestation, histopathology, and outcomes.

Int J Colorectal Dis 2022 Jan 26;37(1):239-250. Epub 2021 Oct 26.

Department of Gastroenterology, Singapore General Hospital, 16 College Road, Block 6 Level 6, Singapore, 169854, Singapore.

Background And Aims: Small bowel adenocarcinoma (SBA) is a rare neoplasm that is associated with Crohn's disease (CD). This study aims to quantify the prevalence of CD-SBA, review the current evidence of histopathology and molecular analysis findings, and identify the clinical presentation and outcomes of CD-SBA.

Methods: Electronic databases Medline and Embase were searched for articles describing SBA in inflammatory bowel disease patients. The histopathology, molecular analysis findings, clinical presentation, prevalence, and outcomes of CD-SBA were extracted, and results were pooled with random effects.

Results: In total, 33 articles were included in the analysis. Prevalence of SBA was 1.15 (CI: 0.31-2.33) per 1000 CD patients. Only 11% (CI: 0.04-0.21) of CD-SBA patients had observable radiological features. CD-SBA was most commonly found in the ileum (84%), diagnosed at stage 2 (36%), with main presenting complaints including obstruction, weight loss, and abdominal pain. Significant histopathological findings included adjacent epithelial dysplasia, and an equal distribution of well-differentiated (49%) and poorly differentiated subtypes (46%). Most prevalent genetic mutation was KRAS mutation (18%), followed by mismatch repair deficiency (9.7%). The 5-year overall survival for CD-SBA patients was 29% (CI: 0.18-0.41), and 33% (CI: 0.26-0.41) for de novo SBA. No statistically significant increase in risk for CD-SBA was noted for treatment with thiopurines, steroids, and 5-ASA.

Conclusion: Our meta-analysis found the prevalence of CD-SBA to be 1.15 per 1000 CD patients. The 5-year overall survival for CD-SBA was poor. The presenting symptoms were non-specific, and therefore the diagnosis requires a high index of suspicion.
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http://dx.doi.org/10.1007/s00384-021-04050-1DOI Listing
January 2022

Statistical Process Control Charts for Monitoring Next-Generation Sequencing and Bioinformatics Turnaround in Precision Medicine Initiatives.

Front Oncol 2021 24;11:736265. Epub 2021 Sep 24.

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Purpose: Precision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes.

Patients And Methods: Trends in NGS and bioinformatics TAT were analyzed using simple regression models with TAT as the dependent variable and chronologically-ordered case number as the independent variable. The M-estimator "robust" regression and negative binomial regression were chosen to serve as sensitivity analyses to each other. Next, two popular statistical process control (SPC) approaches which are CUSUM and EWMA were utilized and the CUSUM log-likelihood ratio (LLR) charts were also generated. All statistical analyses were done in Stata version 16.0 (StataCorp), and nominal P < 0.05 was considered to be statistically significant.

Results: A total of 365 patients underwent successful molecular profiling. Both the robust linear model and negative binomial model showed statistically significant reductions in TAT with accumulating experience. The EWMA and CUSUM charts of overall TAT largely corresponded except that the EWMA chart consistently decreased while the CUSUM analyses indicated improvement only after a nadir at the 82 case. CUSUM analysis found that the bioinformatics team took a lower number of cases (54 cases) to overcome the learning curve compared to the NGS team (85 cases).

Conclusion: As NGS and bioinformatics lead precision oncology into the forefront of cancer management, characterizing the TAT of NGS and bioinformatics processes improves the timeliness of data output by potentially spotlighting problems early for rectification, thereby improving care delivery.
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http://dx.doi.org/10.3389/fonc.2021.736265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498582PMC
September 2021

Antidiabetic Medications for Type 2 Diabetics with Nonalcoholic Fatty Liver Disease: Evidence From a Network Meta-Analysis of Randomized Controlled Trials.

Endocr Pract 2022 Feb 1;28(2):223-230. Epub 2021 Oct 1.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore. Electronic address:

Objective: Type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are closely related, and antidiabetic medications have been shown to be potential therapeutics in NAFLD. Using a network meta-analysis, we sought to examine the effectiveness of antidiabetic agents for the treatment of NAFLD in patients with type 2 diabetes mellitus.

Methods: Medline and Embase were searched for randomized controlled trials relating to the use of antidiabetic agents, including sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor gamma (PPARγ) agonists, biguanides, sulfonylureas and insulin, on NAFLD in patients with diabetes. The p-score was used as a surrogate marker of effectiveness.

Results: A total of 14 articles were included in the analysis. PPARγ agonists were ranked as the best treatment in steatosis reduction, resulting in the greatest reduction of steatosis. There was statistical significance between PPARγ agonists [mean difference (MD): -6.02%, confidence interval (CI): -10.37% to -1.67%] and SGLT2 inhibitors (MD: -2.60%, CI: -4.87% to -0.33%) compared with standard of care for steatosis reduction. Compared with PPARγ agonists, SGLT2 inhibitors resulted in a statistical significant reduction in fibrosis (MD: -0.06, CI: -0.10 to -0.02). Body mass index reduction was highest in SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. Additionally, SGLT2 inhibitors were ranked as the best treatment for increasing high-density lipoprotein and reducing low-density lipoprotein.

Conclusion: Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors were suitable alternatives for the treatment of NAFLD in those with type 2 diabetes mellitus with a reduction in body mass index, fibrosis, and steatosis. SGLT2 inhibitors also have the added benefit of lipid modulation.
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http://dx.doi.org/10.1016/j.eprac.2021.09.013DOI Listing
February 2022

Interactions between epidermal growth factor receptor tyrosine kinase inhibitors and proton-pump inhibitors/histamine type-2 receptor antagonists in non-small cell lung cancer: a systematic review and meta-analysis.

Transl Lung Cancer Res 2021 Aug;10(8):3567-3581

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

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasingly used for advanced non-small cell lung cancer (NSCLC) as first-line therapy. The bioavailability and efficacy of oral EGFR-TKIs could be affected by acid suppression (AS) therapy such as PPIs and H2RAs which are reported to be over-prescribed. Hence, there is a need to investigate the effect of AS on the overall survival (OS), progression-free survival (PFS) and adverse effect profile in patients treated with EGFR TKIs.

Methods: An electronic database search of Medline and Embase was performed following PRISMA guidelines on 17 January 2021. Studies analyzing interactions between EGFR TKIs and PPIs/H2RAs in NSCLC patients were included. Abstracts, non-English or non-Japanese studies or studies using non-EGFR TKIs were excluded. Hazard ratios (HRs) were pooled using generic inverse variance random effects model. Effect sizes for dichotomous variables were pooled using Mantel-Haenszel random effects model. Significance was considered at P≤0.05. Heterogeneity was assessed with Cochran Q-test and I2 test. Publication bias was assessed with funnel plots. The assessment of quality and risk of bias of randomized and non-randomized studies were undertaken with RoB 2 and the ROBINS-I tool respectively.

Results: Out of 1,173 potentially relevant articles, 14 articles were included in the final analysis. The pooled prevalence of AS in patients taking EGFR TKI was 30.71% in 4,010 individuals. Patients who were treated only with EGFR TKI had significantly better OS (HR =1.46, 95% CI: 1.27-1.72; P<0.00001) and PFS (HR =1.63, 95% CI: 1.35-1.98; P<0.00001). The OS for EGFR mutation positive patients only was as similarly significant as the OS in all patients taking EGFR TKI, while the PFS in mutation positive patients was significantly worsened with AS. PPIs resulted in a significantly worsened OS and PFS but H2RAs did not produce significantly different OS and PFS between AS and non-AS users. There were no significant differences in the incidence of rash (OR =0.81, 95% CI: 0.50-1.32; P=0.40), diarrhoea (OR =1.03, 95% CI: 0.63-1.67; P=0.91) or other adverse effects.

Conclusions: Co-administration of AS medications with first-generation EGFR-TKIs in NSCLC worsens survival outcomes. Physicians should only prescribe AS medications when absolutely clinically indicated.
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http://dx.doi.org/10.21037/tlcr-21-378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435386PMC
August 2021

The perspectives of health professionals and patients on racism in healthcare: A qualitative systematic review.

PLoS One 2021 31;16(8):e0255936. Epub 2021 Aug 31.

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

Objective: To understand racial bias in clinical settings from the perspectives of minority patients and healthcare providers to inspire changes in the way healthcare providers interact with their patients.

Methods: Articles on racial bias were searched on Medline, CINAHL, PsycINFO, Web of Science. Full text review and quality appraisal was conducted, before data was synthesized and analytically themed using the Thomas and Harden methodology.

Results: 23 articles were included, involving 1,006 participants. From minority patients' perspectives, two themes were generated: 1) alienation of minorities due to racial supremacism and lack of empathy, resulting in inadequate medical treatment; 2) labelling of minority patients who were stereotyped as belonging to a lower socio-economic class and having negative behaviors. From providers' perspectives, one theme recurred: the perpetuation of racial fault lines by providers. However, some patients and providers denied racism in the healthcare setting.

Conclusion: Implicit racial bias is pervasive and manifests in patient-provider interactions, exacerbating health disparities in minorities. Beyond targeted anti-racism measures in healthcare settings, wider national measures to reduce housing, education and income inequality may mitigate racism in healthcare and improve minority patient care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407537PMC
December 2021

Teaching Medical Research to Medical Students: a Systematic Review.

Med Sci Educ 2021 Apr 8;31(2):945-962. Epub 2021 Jan 8.

Centre for Medical Education, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Phenomenon: Research literacy remains important for equipping clinicians with the analytical skills to tackle an ever-evolving medical landscape and maintain an evidence-based approach when treating patients. While the role of research in medical education has been justified and established, the nuances involving modes of instruction and relevant outcomes for students have yet to be analyzed. Institutions acknowledge an increasing need to dedicate time and resources towards educating medical undergraduates on research but have individually implemented different pedagogies over differing lengths of time.

Approach: While individual studies have evaluated the efficacy of these curricula, the evaluations of educational methods and curriculum design have not been reviewed systematically. This study thereby aims to perform a systematic review of studies incorporating research into the undergraduate medical curriculum, to provide insights on various pedagogies utilized to educate medical students on research.

Findings: Studies predominantly described two major components of research curricula-(1) imparting basic research skills and the (2) longitudinal application of research skills. Studies were assessed according to the 4-level Kirkpatrick model for evaluation. Programs that spanned minimally an academic year had the greatest proportion of level 3 outcomes (50%). One study observed a level 4 outcome by assessing the post-intervention effects on participants. Studies primarily highlighted a shortage of time (53%), resulting in inadequate coverage of content.

Insights: This study highlighted the value in long-term programs that support students in acquiring research skills, by providing appropriate mentors, resources, and guidance to facilitate their learning. The Dreyfus model of skill acquisition underscored the importance of tailoring educational interventions to allow students with varying experience to develop their skills. There is still room for further investigation of multiple factors such as duration of intervention, student voluntariness, and participants' prior research experience. Nevertheless, it stands that mentoring is a crucial aspect of curricula that has allowed studies to achieve level 3 Kirkpatrick outcomes and engender enduring changes in students.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-020-01183-w.
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http://dx.doi.org/10.1007/s40670-020-01183-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368360PMC
April 2021

Systematic review with meta-analysis: The prevalence, risk factors and outcomes of upper gastrointestinal tract Crohn's disease.

Dig Liver Dis 2021 12 16;53(12):1548-1558. Epub 2021 Aug 16.

Department of Gastroenterology, Singapore General Hospital, Singapore, 20 College Road, Academia level 3, Singapore 169856. Electronic address:

Aims: Upper gastrointestinal Crohn's disease (UGI-CD) is an important subclassification of Crohn's Disease (CD). We performed a systematic review and meta-analysis to evaluate the prevalence, risk factors, and clinical outcomes associated with UGI-CD.

Methods: We searched Embase and Medline for articles reporting the clinical information of UGI-CD in CD patients, through 27 October 2020. Disease location and phenotype were coded according to the Montreal classification, and results were pooled with random effects by DerSimonian and Laird model.

Results: 26 articles were included. The prevalence of UGI-CD was 13%. UGI-CD was most commonly found in the stomach (56%) and was associated with concurrent ileocolonic involvement (54%). Non-stricturing, non-penetrating UGI-CD was the most common behavioral phenotype (61%). L4-jejunal disease was associated with the highest rates of surgery. Region of origin did not significantly influence the location and phenotype of UGI-CD. Young, male patients presenting with erythema nodosum, aphthous ulcers and stricturing-phenotype are more likely to have UGI-CD, which in turn is linked to increased risk of hospitalization and surgery.

Conclusion: UGI-CD is present in 13% of patients with CD, and patients with L4-jejunal disease are more likely to require surgery. Further studies examining the effect of ethnicity and region on UGI-CD are needed.
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http://dx.doi.org/10.1016/j.dld.2021.07.037DOI Listing
December 2021

Glucagon-Like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis.

Front Endocrinol (Lausanne) 2021 9;12:609110. Epub 2021 Apr 9.

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

Objective: Non-alcoholic fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus. Studies on glucagon-like peptide-1 receptor agonists for the treatment of non-alcoholic fatty liver disease have reported promising results. Despite this, there has been limited evidence of its efficacy in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. This meta-analysis examined existing evidence on the efficacy of glucagon-like peptide-1 receptor agonists on the management of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

Methods: Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles discussing the efficacy of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Values of standardized mean differences (SMD) and risk ratio (RR) were determined for continuous outcomes and dichotomous outcomes respectively.

Results: 8 studies involving 1,454 patients from 5 randomized controlled trials and 3 cohort studies were included in the analysis. Our analysis found significant improvements in hepatic fat content, liver biochemistry, body composition, glucose parameters, lipid parameters, insulin sensitivity and inflammatory markers following glucagon-like peptide-1 receptor agonist treatment. Glucagon-like peptide-1 receptor agonists significantly decreased hepatic fat content compared to metformin and insulin-based therapies. Glucagon-like peptide-1 receptor agonists also improved fibrosis markers, but this did not reach statistical significance.

Conclusion: With a high prevalence of obesity and non-alcoholic fatty liver disease among patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonist treatment shows promise in improving both diabetes and non-alcoholic fatty liver disease phenotype.
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http://dx.doi.org/10.3389/fendo.2021.609110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063104PMC
January 2022

A Time-Based Meta-Analysis on the Incidence of New Onset Diabetes after Liver Transplantation.

J Clin Med 2021 Mar 3;10(5). Epub 2021 Mar 3.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

NODAT (new-onset diabetes after transplantation) is an important complication after liver transplant, however, there is variation in the reported incidence of NODAT. Therefore, a meta-analysis was performed to estimate the incidence of NODAT in liver transplant. Electronic databases were searched for articles regarding NODAT incidence after liver transplantation. Incidence of NODAT were analyzed at six different timepoints. Summary statistics were calculated using a generalized linear mixed model in random effects. 28 articles were included and out of a pooled population of 71,257 patients, overall incidence of NODAT was found to be 15.51%, 16.09%, 18.30%, 20.86%, 18.08%, 25.05% for three-months, six-months, one-year, three-year, five-year, and ten-year timepoints respectively. After a sensitivity analysis which only included articles with clear definitions of NODAT, the incidence of NODAT was found to be higher at three-year (21.79%), five-year (25.82%), and ten-year (44.95%) timepoints. Subgroup analysis according to ethnicity found no significant differences for all timepoints. However, studies with predominantly Asian participants generally had a higher incidence of NODAT. In conclusion, this meta-analysis provides a pooled estimate of the incidence of NODAT following liver transplantation. Further studies are required to provide a more comprehensive understanding on how ethnicity can affect the incidence of NODAT.
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http://dx.doi.org/10.3390/jcm10051045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959476PMC
March 2021

Risk Factors of Thyroid Eye Disease.

Endocr Pract 2021 Mar 14;27(3):245-253. Epub 2020 Dec 14.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, National University Hospital, Singapore. Electronic address:

Objective: To examine risk factors that might be associated with thyroid eye disease (TED) in patients with Graves' disease (GD), which may guide physicians in the prevention and management of TED.

Methods: Medline and Embase were searched for articles discussing risk factors of TED. Comparisons were made between GD patients with and without TED, and between active and inactive TED GD patients. Weighted mean differences (WMDs) and odds ratios (ORs) were determined for continuous and dichotomous outcomes, respectively. Results were pooled with random effects using the DerSimonian and Laird model.

Results: Fifty-six articles were included in the analysis. Smoking, inclusive of current and previous smoking status, was a significant risk factor for TED (OR: 2.401; CI: 1.958-2.945; P < .001). Statistical significance was found upon meta-regression between male sex and the odds of smoking and TED (β = 1.195; SE = 0.436; P = .013). Other risk factors were also examined, and patients with TED were significantly older than those without TED (WMD: 1.350; CI: 0.328-2.372; P = .010). While both age (WMD: 5.546; CI: 3.075-8.017; P < .001) and male sex (OR: 1.819; CI: 1.178-2.808; P = .007) were found to be significant risk factors for active TED patients compared to inactive TED patients, no statistical significance was found for family history, thyroid status, cholesterol levels, or body mass index.

Conclusion: Factors such as smoking, sex, and age predispose GD patients to TED, and TED patients to active TED. A targeted approach in the management of GD and TED is required to reduce the modifiable risk factor of smoking.
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http://dx.doi.org/10.1016/j.eprac.2020.11.011DOI Listing
March 2021

Sodium-Glucose Co-Transporter 2 Inhibitors for Non-Alcoholic Fatty Liver Disease in Asian Patients With Type 2 Diabetes: A Meta-Analysis.

Front Endocrinol (Lausanne) 2020 11;11:609135. Epub 2021 Feb 11.

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

Objective: Non-alcoholic fatty liver disease (NAFLD) is a very common disorder among patients with type 2 diabetes and may share causal relationship. Type 2 diabetes is a risk factor for progression and potential poor outcomes in NAFLD patients. This meta-analysis aimed to analyze the current evidence of sodium-glucose co-transporter-2 inhibitors (SGLT2i), a glucose-lowering drug to improve NAFLD in patients with Type 2 Diabetes.

Methods: Medline, Embase and Cochrane Central Register of Controlled Trials were searched for articles examining efficacy of SGLT2i on treatments of NAFLD in type 2 diabetes in July 2020, and articles were sieved. Continuous data were extracted in the form of mean and standard deviation and were pooled with standardized mean difference (SMD).

Results: 10 articles involving 555 patients from seven randomized controlled trials (RCTs) and three cohort studies, were included in this meta-analysis. Our analysis revealed significant improvements in hepatic fat content (after treatment: -0.789 (-1.404 to -0.175), p = 0.012; compared with control: -0.923 (-1.562 to -0.285), p = 0.005), AST (After Treatment: -0.539 (-0.720 to -0.357), p < 0.001; compared with control: -0.421 (-0.680 to -0.161), p = 0.001), ALT (after treatment: -0.633 (-0.892 to -0.373), p < 0.001; compared with Control: -0.468 (-0.685 to -0.251), p < 0.001), body composition (BMI: after treatment: -0.225 (-0.456 to 0.005), p = 0.055; compared with Control: -1.092 (-2.032 to -0.153), p = 0.023), glycemic control (HbA1c: After Treatment: -0.701 (-1.098 to -0.303), p = 0.001; compared with control: -0.210 (-0.603 to 0.183), p = 0.295), lipid parameters (Triglycerides: after treatment: -0.230 (-0.409 to -0.052), p = 0.011; compared with control: -0.336 (-0.597 to -0.076), p = 0.011), inflammatory markers (serum ferritin: after treatment: -0.409 (-0.694 to -0.124), p = 0.005; compared with control: -0.814 (-1.688 to 0.059), p = 0.068) after SGLT2i treatment, and when compared against controls. There was a trend in the improvement in fibrosis markers after SGLT2i treatment.

Conclusions: SGLT2i is an effective treatment to improve NAFLD among patients with type 2 diabetes. Further studies are needed to understand the direct and indirect effects of SGLT2i on NAFLD and if SGLT2i could prevent the progression of NAFLD or NASH. SGLT2i could potentially be considered for patients with type 2 diabetes and NAFLD, if there are no contraindications.
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http://dx.doi.org/10.3389/fendo.2020.609135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905212PMC
May 2021

Preoperative concerns of patients undergoing general surgery.

Patient Educ Couns 2021 06 21;104(6):1467-1473. Epub 2020 Nov 21.

Yong Loo Lin School of Medicine, National University Singapore, Singapore; Division of Colorectal Surgery, Department of Surgery, University Surgical Cluster, National University Hospital, Singapore. Electronic address:

Objectives: This qualitative review aims to provide a clearer understanding of concerns general surgery (GS) patients face in the preoperative period.

Methods: Medline, CINAHL, PsycINFO and Web of Science were searched for articles describing the preoperative concerns of GS patients. Qualitative and mixed method studies were included. Key quotes were extracted, coded, and thematically analyzed according to Thomas and Harden's methodology.

Results: 27 articles were included. Three main themes were generated: (1) lead-up to surgery, (2) postoperative recovery process and (3) standard of care. While waiting for surgery, patients were often shrouded with uncertainty and concerned themselves with the potential impacts of their disease and surgery on their wellbeing and recovery. Furthermore, patients' trust and confidence in Healthcare Professionals (HCPs) was compromised when standard of care was perceived to be deficient, resulting in doubts about HCPs' credibility and capabilities.

Conclusion: Patients' preoperative concerns often stem from the uncertainty and unfamiliarity surrounding surgery. To address this, a combination of effective preoperative education, individualised communication and involvement of social support should be considered.

Practice Implications: Preoperative concerns can negatively impact patients and effective interventions will result in a better perioperative experience with fewer negative consequences arising from patients' fear and anxiety.
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http://dx.doi.org/10.1016/j.pec.2020.11.010DOI Listing
June 2021
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