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Xiu-Li Lim,1,* Boon-Wee Teo,2,* Bee-Choo Tai,1 Tien Y Wong,3 Daniel P-K Ng1 1Department of Epidemiology and Public Health, 2Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, 3Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore*Joint first authorsBackground: The main objective of this study was to investigate whether plasma pentosidine levels were associated with cataract and low estimated glomerular filtration rate (eGFR) in nonproteinuric type 2 diabetic patients.Methods: We characterized 888 nonproteinuric type 2 diabetic patients residing in Singapore according to their eGFR values. Proteinuria was excluded on the basis of multiple urinalyses. Patients with low renal function (cases, n = 125) and controls (n = 763) were defined as having eGFR < and ≥60 mL/min/1.73 m2, respectively. Pentosidine levels were measured by enzyme-linked immunosorbent assay. Multinomial logistic regression was used to test the association between plasma pentosidine levels and the joint phenotype of cataract and low eGFR.Results: Cases had higher triacylglycerol values, higher systolic blood pressure, and were more likely to be treated with two or more antihypertensive medications. In univariate analysis, cases were potentially more than twice as likely to have had a history of cataract compared with controls. This association persisted in multivariate analyses after adjusting for the significant covariates, hypertension and triacylglycerol, but was attenuated when age was included in the model. Plasma pentosidine levels were significantly higher in cases with low eGFR who also had a history of cataract. This association persisted in multivariate analyses that included the covariates, glycosylated hemoglobin, hypertension, and diabetic retinopathy, as well as age.Conclusion: Carbonyl stress, as reflected by pentosidine levels, is present in a subset of nonproteinuric diabetic patients. Clinically, this stress was associated with the joint presence of cataract and low eGFR.Keywords: advanced glycation endproducts, Chinese, normoalbuminuria, renal function

Background: We investigated the prevalence and predictors of obstructive sleep apnea (OSA) in patients admitted to the hospital for acute myocardial infarction and whether OSA has any association with microvascular perfusion after primary percutaneous coronary intervention (PCI).Methods: Recruited patients were scheduled to undergo an overnight sleep study between 2 and 5 days after primary PCI. An apnea-hypopnea index (AHI) of > or = 15 was considered diagnostic of OSA. Impaired microvascular perfusion after primary PCI was defined as an ST-segment resolution of < or = 70%, myocardial blush grade 0 or 1, or a corrected Thrombolysis in Myocardial Infarction (TIMI) [antegrade flow scale] frame count > 28.Results: Sleep study was performed in 120 patients and completed in 105 patients (study cohort, mean age 53 +/- 10 years, male 98%) with uncomplicated myocardial infarction. An AHI was > or = 15 in 69 patients (OSA-positive), giving a prevalence of 65.7%. Diabetes mellitus was found to be a significant risk factor for OSA (odds ratio, 2.86; 95% confidence interval, 1.06 to 8.24; p = 0.033). There were no differences between OSA-positive and OSA-negative groups with regard to the percentage of patients with < or = 70% ST-segment resolution (73% vs 64%, respectively; p = 0.411), myocardial blush grade 0 or 1 (39.1% vs 38.9%, respectively; p = 1.000), or corrected TIMI frame count > 28 (21.7% vs 25.0%, respectively; p = 0.807).Conclusions: We found a high prevalence of previously undiagnosed OSA in patients admitted with acute myocardial infarction. Diabetes mellitus was independently associated with OSA. No evidence indicated that OSA is associated with impaired microvascular perfusion after primary PCI. [ABSTRACT FROM AUTHOR]

Objective: A key consideration when setting up genetic studies is the case definition. For diabetic nephropathy, the case definition is typically based on the presence of albuminuria. However, it has been long debated whether diabetic nephropathy cases defined in this way may have a high prevalence of nondiabetic kidney disease, especially if diabetic retinopathy is absent.Research Design and Methods: We performed a meta-analysis of 53 studies comprising 17,791 subjects investigating the angiotensin-I converting enzyme insertion/deletion polymorphism, taking into account the requirement for diabetic retinopathy in the case definition and assuming a random-effects model.Results: No publication bias was observed. The overall pooled odds ratio (OR) for all 53 studies was 0.78 (95% CI 0.70-0.87; P < 0.001), which indicated a significant protection against diabetic nephropathy for genotype II compared with carriage of the D-allele. The pooled OR for the 11 studies (n = 3,413) requiring diabetic retinopathy in the case definition was 0.68 (0.53-0.86; P = 0.002), and this was not significantly different from the pooled OR of 0.81 (0.71-0.92; P = 0.001) obtained from the 42 remaining studies (n = 14,378) (P = 0.198). This lack of any significant effect of diabetic retinopathy was reiterated in subgroup analyses based on the type of diabetes present.Conclusions: Stipulating the presence of diabetic retinopathy in the case definition of diabetic nephropathy did not appear to confer tangible benefits when detecting genetic associations. Besides reducing sample sizes, this stipulation makes the interpretation of genetic associations more difficult due to the potential confounding presence of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Background: The prospective association between sleep duration and the development of late-life depressive symptomology is unclear., Aims: To investigate sleep duration from midlife to late life in relation to risk of depressive symptoms in late life., Method: A total of 14 361 participants from the Singapore Chinese Health Study were included in the present study. Daily sleep duration was self-reported at baseline (mean age of 52.4 years; 1993-98), follow-up 2 (mean age of 65.2 years; 2006-10) and follow-up 3 (mean age of 72.5 years; 2014-16) interviews. Depressive symptoms were evaluated using the Geriatric Depression Scale at follow-up 3 interviews. Modified Poisson regression models were performed to estimate relative risks and 95% confidence intervals of late-life depressive symptoms in relation to sleep duration at baseline and the two follow-up interviews., Results: Compared with sleeping 7 h per day, a short sleep duration of ≤5 h per day at baseline (i.e. midlife) was related to a higher risk of depressive symptoms (relative risk 1.10, 95% CI 1.06-1.15), and this risk was not affected by subsequent prolongation of sleep. Conversely, a long sleep duration of ≥9 h per day at baseline was not related to risk of depressive symptoms. At follow-up 3 (i.e. late life), both short sleep (relative risk 1.20, 95% CI 1.16-1.25) and long sleep (relative risk 1.12, 95% CI 1.07-1.18) duration were cross-sectionally associated with depressive symptoms., Conclusion: Short sleep duration in midlife, regardless of subsequent prolongation, is associated with an increased risk of depression in late life. Contrariwise, both short and long sleep duration in late life co-occur with depressive symptoms.

Introduction: Myopericarditis is a rare but serious coronavirus disease 2019 (COVID-19) vaccine-related adverse event primarily affecting adolescents. Given recent approvals for childhood vaccination, we performed a meta-analysis investigating myopericarditis following messenger ribonucleic acid COVID-19 vaccination in children aged <19 years, focusing on its overall risk and high-risk subgroups., Methods: We searched MEDLINE via PubMed, Embase and Scopus from inception to 1 August 2022 for observational studies reporting myopericarditis in temporal relation to paediatric COVID-19 vaccination. We conducted random-effects meta-analyses (DerSimonian and Laird) on myopericarditis (primary outcome), myocarditis and pericarditis (secondary outcomes)., Results: Of 2115 studies, 12 (59,229,160 doses) studies were included in our analysis. There were 19.8 (95% confidence interval [CI]: 10.4-37.6) myopericarditis cases reported per million doses in children, compared to 23.7 (95% CI: 12.2-46.1) cases in adults (eight studies, 376,899,888 doses; P = 0.70). Compared to the second dose (34.4, 95% CI: 15.2-77.8), the number of cases post-first dose was significantly lower (9.1, 95% CI: 4.4-18.8; P = 0.017), while the number of cases post-third dose was not higher than that of post-second dose (28.4, 95% CI: 10.4-61.8; P = 0.57, global P = 0.031). Males were at higher risk of myopericarditis (67.4, 95% CI: 36.5-124.5) than females (6.9, 95% CI: 3.1-15.3; P < 0.0001). Finally, the number of cases was higher (overall P < 0.0001) among children aged ≥12 years (39.9, 95% CI: 24.1-66.0) than among children aged <12 years (3.0, 95% CI: 2.3-3.9)., Conclusion: Our meta-analysis showed 19.8 cases of myopericarditis per million doses among children, not significantly different from that of adults. Higher risk subgroups included adolescents, males, and those receiving their second dose of vaccination., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Objective: To characterise lifestyle patterns (comprising dietary and movement behaviour aspects) of children in Singapore and examine the correlates of these patterns., Design: An observational study approach was used. Children recorded their diet and activities over two weekdays and two weekend days on a validated web-based assessment, My E-Diary for Activities and Lifestyle (MEDAL). Lifestyle patterns were derived using principal component analysis, and the correlations of these with multiple known determinants organised by distal, intermediate, and proximal levels of influence were studied., Setting: Children of the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort., Participants: Ten-year-old children (n = 397)., Results: Three lifestyle patterns, "high snacks and processed food", "balanced" and "mixed", were identified. We focused on the more health-promoting "balanced" pattern, characterised by lower screen-viewing and higher consumption of fruits, vegetables, wholegrains, and dairy. Among the distal factors, girls were more adherent to the "balanced" pattern compared to boys, and children of parents with lower education levels were less adherent to this pattern. Among intermediate factors, children of mothers with higher diet quality were more adherent to the "balanced" pattern. Among the proximal factors, engagement in active transport, leisure sports, and educational activities outside of school were positively associated with the "balanced" pattern, whereas screen-viewing while travelling was negatively associated with this pattern. Having siblings, pet ownership, mother's physical activity, parenting style, parental bonding, child's outdoor time, and breakfast consumption were not associated with children's lifestyle patterns., Conclusions: These findings provide direction for future interventions by identifying vulnerable groups and contexts that should be prioritised., (© 2024. The Author(s).)

Background: Dependency on screen viewing (SV) has reached unprecedented levels, and mental health issues are becoming a major public health concern. However, the associations between SV, including variations in purposes, devices, and timing, and mental health remain unclear. This study aims to provide insights into these associations among university students., Methods: This analysis used baseline data from a longitudinal cohort study among first-year university students matriculating in the 2021-2022 academic year. Self-reported data on sociodemographics, health behaviors and mental health outcomes alongside anthropometric measurements were collected. Unadjusted and adjusted logistic regression analyses were conducted., Results: The average age of the 997 valid students was 20.2 years, with 59.6% being female and 41.4% male. Students spent 14.3 h daily on SV, with females reporting higher SV than males. Daily SV was predominant for study purposes (7.6 h/day). Computer usage was the highest (7.0 h/day), while TV usage was the lowest (1.7 h/day). Poor mental wellbeing was reported by 33.6% of students, while 13.9% experienced psychological distress. Compared to students with low total SV, those with high levels were more likely to have poor mental wellbeing [OR (95% CI): 1.40 (0.99, 1.98)] and psychological distress [1.56 (1.00, 2.44)]. High levels of recreational and study related SV were significantly associated with poor mental wellbeing [1.81 (1.27, 2.56)] and psychological distress [1.75 (1.11, 2.83)], respectively. Those with high levels of computer time were more likely to have poor mental wellbeing [1.44 (1.01, 2.06)], and high weekend day SV was associated with greater odds of psychological distress [2.16 (1.17, 4.06)]., Conclusions: SV among university students was high, as was the high prevalence of poor mental wellbeing and psychological distress. Greater SV was associated with poor mental wellbeing and psychological distress. Differences according to purpose of SV were noted. Although recreational SV was associated with poor mental wellbeing, study related SV was associated with psychological distress. Variations across different devices and timing were also noted. This highlights the need for further longitudinal research to understand the impact of SV on mental health and to guide interventions for promoting mental health of university students globally., (© 2024. The Author(s).)

Preclinical and limited epidemiological studies suggest that oxidative stress may be implicated in geriatric depression. Our study investigated the association between midlife dietary total antioxidant capacity (TAC) and depressive symptoms in late life among 13,712 participants in a population-based cohort of Chinese in Singapore. At baseline (1993-1998), intake of antioxidants from diet and supplements at a mean age of 52.4 years was estimated using a validated food frequency questionnaire to derive two dietary TAC indices from vitamins C and E, carotenoids and flavonoids: the Comprehensive Dietary Antioxidant Index (CDAI) and Vitamin C Equivalent Antioxidant Capacity (VCEAC). At follow-up 3 (2014-2016), when participants were at a mean age of 72.5 years, depressive symptoms were assessed using the Geriatric Depression Scale, and depression, defined as having ≥5 symptoms, was presented in 3173 (23.1%) participants. Both CDAI and VCEAC indices were inversely associated with odds of depressive symptoms in a stepwise manner: the OR (95% CI) comparing the extreme quartiles was 0.73 (0.64-0.83; P trend < 0.01) for the CDAI and 0.77 (0.68-0.87; P trend < 0.01) for the VCEAC. Specifically, higher intakes of vitamin C, carotenoids, and flavonoids were associated with a lower likelihood of depressive symptoms. Our findings support the recommendation of an antioxidant-rich diet for the prevention of depression.

This study aim to investigate if remote intensive coaching for the first 6 months post-AMI will improve adherence to the twice-a-day antiplatelet medication, ticagrelor. Between July 8, 2015, to March 29, 2019, AMI patients were randomly assigned to remote intensive management (RIM) or standard care (SC). RIM participants underwent 6 months of weekly then two-weekly consultations to review medication side effects and medication adherence coaching by a centralized nurse practitioner team, whereas SC participants received usual cardiologist face-to-face consultations. Adherence to ticagrelor were determined using pill counting and serial platelet reactivity measurements for 12 months. A total of 149 (49.5%) of participants were randomized to RIM and 152 (50.5%) to SC. Adherence to ticagrelor was similar between RIM and SC group at 1 month (94.4 ± 0.7% vs. 93.6±14.7%, p = 0.537), 6 months (91.0±14.6% vs. 90.6±14.8%, p = 0.832) and 12 months (87.4±17.0% vs. 89.8±12.5%, p = 0.688). There was also no significant difference in platelet reactivity between the RIM and SC groups at 1 month (251AU*min [212-328] vs. 267AU*min [208-351], p = 0.399), 6 months (239AU*min [165-308] vs. 235AU*min [171-346], p = 0.610) and 12 months (249AU*min [177-432] vs. 259AU*min [182-360], p = 0.678). Sensitivity analysis did not demonstrate any association of ticagrelor adherence with bleeding events and major adverse cardiovascular events. RIM, comprising 6 months of intensive coaching by nurse practitioners, did not improve adherence to the twice-a-day medication ticagrelor compared with SC among patients with AMI. A gradual decline in ticagrelor adherence over 12 months was observed despite 6 months of intensive coaching., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Diabetes and hypertension are prevalent and costly to the health system. We have developed a mobile app (EMPOWER app) which enables remote monitoring and education through personalised nudges. We aim to study the effectiveness of a multi-component intervention comprising the EMPOWER mobile app with health coaching and shared decision-making for diabetes and hypertension., Methods: We will conduct a two-arm, open-label, pragmatic randomised controlled trial (RCT). Participants with comorbid diabetes and hypertension enrolled from public primary care clinics will be randomised to either intervention or control in a 1:1 ratio. The intervention group participants will have access to health coaching with shared decision-making interventions in addition to the EMPOWER app and their usual primary care. The control group participants will continue to receive usual primary care and will neither receive the EMPOWER app nor health coaching and shared decision-making interventions. Our primary outcome is change in HbA1c level over 9 months. Secondary outcomes include change in systolic blood pressure, quality of life, patient activation, medication adherence, physical activity level, diet, and healthcare cost (direct and indirect) over 9 months., Discussion: Our trial will provide key insights into clinical- and cost-effectiveness of a multi-component intervention comprising EMPOWER mobile app, health coaching and shared decision-making in diabetes and hypertension management. This trial will also offer evidence on cost-effective and sustainable methods for promoting behavioural changes among patients with comorbid diabetes and hypertension., Trial Registration: This study was registered on clintrials.gov on August 3, 2022, with the trial registration number: NCT05486390., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kwan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are malignancies that demonstrate nerve sheath differentiation in the peripheral nervous system. They can occur sporadically or be associated with neurofibromatosis type 1 (NF1), an autosomal dominant neurocutaneous disorder, with up to 13% of patients developing MPNSTs in their lifetimes. Previous studies have suggested conflicting findings regarding the prognosis of NF1 for patients with MPNSTs. The elucidation of NF1 as an independent prognostic factor on mortality has implications for clinical management. We aim to investigate the role of NF1 status as an independent prognostic factor of overall survival (OS) and disease-specific survival (DSS) in MPNSTs., Methods: An electronic literature search of PubMed and MEDLINE was performed on studies reporting OS or DSS outcomes of MPNSTs with and without NF1. A grey literature search by reviewing bibliographies of included studies and review articles was performed to find pertinent studies. Data was extracted and assessed in accordance with the PRISMA guidelines. A meta-analysis was performed to calculate hazard ratios (HRs) using a random-effects model. The primary and secondary outcomes were all-cause and disease-specific mortality, respectively, with NF1 as an independent prognostic factor of interest., Results: A total of 59 retrospective studies involving 3602 patients fulfilled the inclusion criteria for OS analysis, and 23 studies involving 704 MPNST patients were included to evaluate DSS outcomes. There was a significant increase in the hazard of all-cause mortality (HR 1.63, 95% CI 1.45 to 1.84) and disease-specific mortality (HR 1.52, 95% CI 1.24 to 1.88) among NF1 as compared to sporadic cases. Subgroup analyses and meta-regression showed that this result was consistent regardless of the quality of the study and year of publication., Conclusion: NF1 is associated with a substantially higher risk of all-cause and disease-specific mortality. This finding suggests that closer surveillance is required for NF1 patients at risk of developing MPNSTs., (© 2024. The Author(s).)

Background: Selecting the smaller kidney for donation has been advocated if there is a size difference of > 10% between the 2 kidneys but has never been prospectively evaluated. With increase in donor nephrectomies, it is important to evaluate this to minimize loss of renal function to donors., Methods: 75 consecutive donor nephrectomy patients were included in our longitudinal study. The Split Renal Volume (SRV) of bilateral kidneys were measured using contrasted computer tomography scans and patients segregated into 2 groups depending on donated kidney having more (Group 1) or less than (Group 2) 52.5% of SRV., Results: Patients in Group 1 (n = 19) and 2 (n = 56) were of similar age (43.8 vs. 48.3), BMI (22.4 vs. 25.2), sex (57.9 vs. 55.4% women), respectively. Although total kidney volumes were similar in both groups, Group 1 had significantly smaller right kidney volumes (120.4 ± 24.9 vs. 142.7 ± 28.4 mls, p = 0.003). EGFR pre-operatively (116.3 ± 20.8 vs. 106.3 ± 23.8 mL/min/1.73 m 2 ) and at 6-months (65.7 ± 13.3 vs. 66.9 ± 15.5 mL/min/1.73 m 2 ) were not different between groups. However, patients in Group 1 had significantly greater absolute (50.6 ± 14.9 vs. 39.5 ± 14.7 mL/min/1.73 m 2 ) and relative decline (43.0 ± 8.6 vs. 36.3 ± 10.6%) in eGFR at 6 months (p = 0.06, 0.009)., Conclusion: With a SRV difference of 5% between the 2 sides, removal of the larger kidney for living kidney donation resulted in greater early decline of renal function than kidney donors whose larger or equivalent kidney is preserved., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Diabetes mellitus (DM) is the third most common chronic condition associated with frequent hospital readmissions. Predictors of the number of readmissions within 1 year among patients with DM are less often studied compared with those of 30-day readmission. This study aims to identify predictors of number of readmissions within 1 year amongst adult patients with DM and compare different count regression models with respect to model fit. Data from 2008 to 2015 were extracted from the electronic medical records of the National University Hospital, Singapore. Inpatients aged ≥ 18 years at the time of index admission with a hospital stay > 24 h and survived until discharge were included. The zero-inflated negative binomial (ZINB) model was fitted and compared with three other count models (Poisson, zero-inflated Poisson and negative binomial) in terms of predicted probabilities, misclassification proportions and model fit. Adjusted for other variables in the model, the expected number of readmissions was 1.42 (95% confidence interval [CI] 1.07 to 1.90) for peripheral vascular disease, 1.60 (95% CI 1.34 to 1.92) for renal disease and 2.37 (95% CI 1.67 to 3.35) for Singapore residency. Number of emergency visits, number of drugs and age were other significant predictors, with length of stay fitted as a zero-inflated component. Model comparisons suggested that ZINB provides better prediction than the other three count models. The ZINB model identified five patient characteristics and two comorbidities associated with number of readmissions. It outperformed other count regression models but should be validated before clinical adoption., (© 2023. The Author(s).)

Background: Good physical and mental health are essential for healthy ageing. Holistic mobile health (mHealth) interventions-including at least three components: physical activity, diet, and mental health-could support both physical and mental health and be scaled to the population level. This review aims to describe the characteristics of holistic mHealth interventions and their effects on related behavioural and health outcomes among adults from the general population., Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, Scopus, China National Knowledge Infrastructure, and Google Scholar (first 200 records). The initial search covered January 1, 2011, to April 13, 2022, and an updated search extended from April 13, 2022 to August 30, 2023. Randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) were included if they (i) were delivered via mHealth technologies, (ii) included content on physical activity, diet, and mental health, and (iii) targeted adults (≥18 years old) from the general population or those at risk of non-communicable diseases (NCDs) or mental disorders. Studies were excluded if they targeted pregnant women (due to distinct physiological responses), individuals with pre-existing NCDs or mental disorders (to emphasise prevention), or primarily utilised web, email, or structured phone support (to focus on mobile technologies without exclusive human support). Data (summary data from published reports) extraction and risk-of-bias assessment were completed by two reviewers using a standard template and Cochrane risk-of-bias tools, respectively. Narrative syntheses were conducted for all studies, and random-effects models were used in the meta-analyses to estimate the pooled effect of interventions for outcomes with comparable data in the RCTs. The study was registered in PROSPERO, CRD42022315166., Findings: After screening 5488 identified records, 34 studies (25 RCTs and 9 pre-post NRSIs) reported in 43 articles with 5691 participants (mean age 39 years, SD 12.5) were included. Most (91.2%, n = 31/34) were conducted in high-income countries. The median intervention duration was 3 months, and only 23.5% (n = 8/34) of studies reported follow-up data. Mobile applications, short-message services, and mobile device-compatible websites were the most common mHealth delivery modes; 47.1% (n = 16/34) studies used multiple mHealth delivery modes. Of 15 studies reporting on weight change, 9 showed significant reductions (6 targeted on individuals with overweight or obesity), and in 10 studies reporting perceived stress levels, 4 found significant reductions (all targeted on general adults). In the meta-analysis, holistic mHealth interventions were associated with significant weight loss (9 RCTs; mean difference -1.70 kg, 95% CI -2.45 to -0.95; I 2  = 89.00%) and a significant reduction in perceived stress levels (6 RCTs; standardised mean difference [SMD] -0.32; 95% CI -0.52 to -0.12; I 2  = 14.52%). There were no significant intervention effects on self-reported moderate-to-vigorous physical activity (5 RCTs; SMD 0.21; 95%CI -0.25 to 0.67; I 2  = 74.28%) or diet quality scores (5 RCTs; SMD 0.21; 95%CI -0.47 to 0.65; I 2  = 62.27%). All NRSIs were labelled as having a serious risk of bias overall; 56% (n = 14/25) of RCTs were classified as having some concerns, and the others as having a high risk of bias., Interpretation: Findings from identified studies suggest that holistic mHealth interventions may aid reductions in weight and in perceived stress levels, with small to medium effect sizes. The observed effects on diet quality scores and self-reported moderate-to-vigorous physical activity were less clear and require more research. High-quality RCTs with longer follow-up durations are needed to provide more robust evidence. To promote population health, future research should focus on vulnerable populations and those in middle- and low-income countries. Optimal combinations of delivery modes and components to improve efficacy and sustain long-term effects should also be explored., Funding: National Research Foundation, Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE) Programme and Physical Activity and Nutrition Determinants in Asia (PANDA) Research Programme., Competing Interests: TK is affiliated with the Centre for Digital Health Interventions (CDHI), a joint initiative of the Institute for Implementation Science in Health Care, University of Zürich, the Department of Management, Technology, and Economics at ETH Zürich, and the Institute of Technology Management and School of Medicine at the University of St. Gallen. CDHI is funded in part by CSS, a Swiss health insurer. He is also a cofounder of Pathmate Technologies, a university spin-off company that creates and delivers digital clinical pathways. However, neither CSS nor Pathmate Technologies was involved in this research., (© 2023 The Author(s).)

Background: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study., Methods: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability., Results: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications., Conclusion: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC., Competing Interests: Declaration of Competing Interest J SJ Lim: Honoraria and consulting – Astrazeneca, Roche, DKSH, MSD, Eisai, Novartis, Pfizer, Gilead Pharmaceuticals, Research funding – CTI Biopharma, Trael – AZD, Pfizer; A LA Wong: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eisai, DKSH, Research funding – Otsuka Pharmaceuticals; S GW Ow: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche; R Sundar: Honoraria and consulting - Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas, Pierre-Fabre, Eili Lilly, BMS, Roche, Astra Zeneca, Ipsen; Research funding – Paxman Coolers, MSD, Natera; Patents – Paxman, Auristone; Travel – Roche, Astra Zeneca, Taiho, Eisai, DKSH. BC Tai: Honoraria and consulting – Boehringer Ingelheim, Royalty – Wiley-Blackwell; SC Lee: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche, ACT Genomics, Eisai, research funding – Taiho, Eisai, Pfizer, ACT Genomics. G HJ Chan, Y LE Ang, WQ Chong, M Lee, JL Low and J RE Choo, have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Epidermal growth factor receptor ( EGFR ) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44-3.12) years. The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

Purpose of Review: The development of potent novel agents has improved outcomes for patients with multiple myeloma (MM). Heterogeneity of response to therapy, an expanding arsenal of treatment options, and cost are however major challenges for physicians making treatment decisions. Response-adapted therapy is hence an attractive strategy for sequencing of therapy in MM. Despite its successful application in other haematologic malignancies, response-adapted therapy is yet to become a standard of care for MM. We provide our perspective on response-adapted therapeutic strategies evaluated thus far and how they may be implemented and improved on in treatment algorithms of the future., Recent Findings: While older studies suggested that early response based on International Myeloma Working Group response criteria could impact long-term outcomes, recent data have contradicted these findings. The advent of minimal residual disease (MRD) as a powerful prognostic factor in MM has raised the promise of MRD-adapted treatment strategies. The development of more sensitive techniques for paraprotein quantification as well as imaging modalities to detect extramedullary disease is likely to change response assessment in MM. These techniques combined with MRD assessment may provide sensitive and holistic response assessments which could be evaluated in clinical trials. Response-adapted treatment algorithms have the potential to allow an individualised treatment strategy, maximising efficacy, while minimising toxicities and cost. Standardisation of MRD methodology, incorporation of imaging into response assessment, and the optimal management of MRD positive patients are key questions to be addressed in future trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To assess the effect of aromatherapy with lavender oil alone, and in combination with music, on pain and anxiety during extracorporeal shockwave lithotripsy for kidney stones., Methods: This was a single-centre prospective, randomised controlled trial. The subjects were block randomised into 3 study groups, Group 1: Control; Group 2: Aromatherapy only; Group 3: Aromatherapy and music. All subjects were given patient-controlled intravenous alfentanil as standard analgesia. The primary outcome measures were pain and anxiety scores using visual analogue scale (VAS) and State-Trait Anxiety Inventory., Results: Ninety patients were recruited and randomised prospectively into Group 1 (n = 30), Group 2 (n = 30), and Group 3 (n = 30). For pain outcome, both Group 2 and Group 3 showed a trend towards lower mean VAS pain scores of 2.73 in both groups compared to the control with a mean VAS score of 3.50, but it was not statistically significant (p = 0.272). There was no significant difference in anxiety scores between groups post-treatment., Conclusions: Our study was unable to show a significant improvement in pain relief and anxiety when aromatherapy with lavender oil was added to standard analgesia alone during shockwave lithotripsy. There was also no difference when aromatherapy was combined with music., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC)., Methods: We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 μg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events., Results: Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55-1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34-1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI -0.50 to 1.60), and AIx (AMD 0.13, 95% CI -3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD -86, 95% CI -854 to -117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio = 0.98, 95% CI 0.50-1.94)., Conclusion: Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population., Methods: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020., Results: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic., Conclusions: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date., (© 2023. The Author(s).)

Background: Sedentary behaviour increases the risks of non-communicable diseases. The objective of this trial was to evaluate the effect of the Physical Activity at Work multicomponent intervention to reduce sedentary behaviour in Thai office workers., Methods: Offices under the Ministry of Public Health Thailand, were randomly allocated to the intervention and control group in a 1:1 ratio, stratified by office size. The intervention included individual (pedometer and lottery-based financial incentives), social (group movement breaks), environmental (posters), and organisational (leader encouragement) components. At baseline and 6-month follow-up, participants wore ActiGraph TM on the waist for ten days. The primary outcome was the between-group difference in sedentary time at 6-month, analysed using a linear mixed-effects model. Other outcomes were physical activity, biomarkers, productivity, and musculoskeletal health. Trial registration: The PAW study was registered at the Thai Clinical Trials Registry (ID TCTR20200604007) on 02 June 2020., Findings: 282 office workers were recruited and randomly allocated to the control group (142 participants, nine offices) and the intervention group (140 participants, nine offices). The mean age was 38.6 years (SD = 10.4), and 81% were women. There was no evidence of intervention effects on sedentary time during waking hours (-26.8; 95% CI = -69.2 to 15.7 min), physical activity levels, or biomarkers between groups at 6-month. In the adjusted analysis, increases in time spent in moderate-to-vigorous physical activity (5.45; 95% CI = -0.15 to 11.1 min) and step count (718; 95% CI = -45 to 1481 steps) during waking hours were observed, although there was no evidence of a difference between groups., Interpretation: The intervention did not significantly reduce sedentary time in Thai office workers. Suboptimal intervention uptake due to Covid-19 pandemic restrictions and loss of statistical power associated with recruitment constraints may explain this result. Further investigations are needed to evaluate the processes of the trial., Funding: The Thai Health Promotion Foundation and the International Decision Support Initiative (iDSI)., Competing Interests: The authors do not have conflicts of interest to report., (© 2022 The Authors.)

Objective: The primary objective is to develop a prediction model of 30-day hospital readmission among adults with diabetes mellitus (DM) whose index admission was DM-related. The secondary aims are to internally and externally validate the prediction model and compare its performance with 2 existing models., Research Design and Setting: Data of inpatients aged ≥ 18 years from 2008 to 2015 were extracted from the electronic medical record system of the National University Hospital, Singapore. Unplanned readmission within 30 days was calculated from the discharge date of the index hospitalization. Multivariable logistic regression and 10-fold cross-validation were performed. For external validation, simulations based on prevalence of 30-day readmission, and the regression coefficients provided by referenced papers were conducted., Results: Eleven percent of 2355 patients reported 30-day readmission. The prediction model included 4 predictors: length of stay, ischemic heart disease, peripheral vascular disease, and number of drugs. C-statistics for the prediction model and 10-fold cross-validation were 0.68 (95% CI 0.66, 0.70) and 0.67 (95% CI 0.63 to 0.70), respectively. Those for the 3 simulated external validation data sets ranged from 0.64 to 0.68., Conclusion: The prediction model performs well with good internal and external validity for identifying patients with DM at risk of unplanned 30-day readmission., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Myopericarditis is a rare complication of vaccination. However, there have been increasing reports of myopericarditis following COVID-19 vaccination, especially among adolescents and young adults. We aimed to characterise the incidence of myopericarditis following COVID-19 vaccination, and compare this with non-COVID-19 vaccination., Methods: We did a systematic review and meta-analysis, searching four international databases from Jan 1, 1947, to Dec 31, 2021, for studies in English reporting on the incidence of myopericarditis following vaccination (the primary outcome). We included studies reporting on people in the general population who had myopericarditis in temporal relation to receiving vaccines, and excluded studies on a specific subpopulation of patients, non-human studies, and studies in which the number of doses was not reported. Random-effects meta-analyses (DerSimonian and Laird) were conducted, and the intra-study risk of bias (Joanna Briggs Institute checklist) and certainty of evidence (Grading of Recommendations, Assessment, Development and Evaluations approach) were assessed. We analysed the difference in incidence of myopericarditis among subpopulations, stratifying by the type of vaccine (COVID-19 vs non-COVID-19) and age group (adult vs paediatric). Among COVID-19 vaccinations, we examined the effect of the type of vaccine (mRNA or non-mRNA), sex, age, and dose on the incidence of myopericarditis. This study was registered with PROSPERO (CRD42021275477)., Findings: The overall incidence of myopericarditis from 22 studies (405 272 721 vaccine doses) was 33·3 cases (95% CI 15·3-72·6) per million vaccine doses, and did not differ significantly between people who received COVID-19 vaccines (18·2 [10·9-30·3], 11 studies [395 361 933 doses], high certainty) and those who received non-COVID-19 vaccines (56·0 [10·7-293·7], 11 studies [9 910 788 doses], moderate certainty, p=0·20). Compared with COVID-19 vaccination, the incidence of myopericarditis was significantly higher following smallpox vaccinations (132·1 [81·3-214·6], p<0·0001) but was not significantly different after influenza vaccinations (1·3 [0·0-884·1], p=0·43) or in studies reporting on various other non-smallpox vaccinations (57·0 [1·1-3036·6], p=0·58). Among people who received COVID-19 vaccines, the incidence of myopericarditis was significantly higher in males (vs females), in people younger than 30 years (vs 30 years or older), after receiving an mRNA vaccine (vs non-mRNA vaccine), and after a second dose of vaccine (vs a first or third dose)., Interpretation: The overall risk of myopericarditis after receiving a COVID-19 vaccine is low. However, younger males have an increased incidence of myopericarditis, particularly after receiving mRNA vaccines. Nevertheless, the risks of such rare adverse events should be balanced against the risks of COVID-19 infection (including myopericarditis)., Funding: None., Competing Interests: Declaration of interests KR has received honoraria for webinars unrelated to the topic from Baxter. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Existing modes of collecting self-reported 24-hour movement information from children, including digital assessments, have not been demonstrated to be of acceptable validity when compared to objective measurements. My E-Diary for Activities and Lifestyle (MEDAL) is an interactive web-based diary developed to collect time-use information from children aged 10 years and older., Objective: This study evaluated the validity of MEDAL for assessing children's movement behaviors by comparing self-reported and accelerometer-measured time spent in movement behavior among children in Singapore aged 10-11 years., Methods: Funding for this study was obtained in October 2017, and data were collected between April and August 2020. Participants recorded their daily activities using MEDAL over 2 specified weekdays and 2 weekend days and wore an Actigraph accelerometer on their nondominant wrist throughout the study to objectively assess movement behaviors. Spearman correlation coefficient and intraclass correlation coefficient (ICC) were used to compare the accelerometer measurements and self-reports for each movement behavior. Bland-Altman plots were generated to investigate trends of bias in the self-reports., Results: Among the participants aged 10-11 years (29/49, 59% boys), we observed that children reported lower light physical activity (LPA) and higher moderate-to-vigorous physical activity (MVPA), inactivity, and night sleep than that measured by the accelerometer. There was a moderate-to-strong correlation between self-reported and accelerometer-measured MVPA (r=0.37; 95% CI 0.20-0.54), inactivity (r=0.36; 95% CI 0.18-0.54), and night sleep (r=0.58; 95% CI 0.43-0.74); the correlation for LPA was poor (r=0.19; 95% CI 0.02-0.36). Agreement was poor for all behaviors (MVPA: ICC=0.24, 95% CI 0.07-0.40; LPA: ICC=0.19, 95% CI 0.01-0.36; inactivity: ICC=0.29, 95% CI 0.11-0.44; night sleep: ICC=0.45, 95% CI 0.29-0.58). There was stronger correlation and agreement on weekdays for inactivity and night sleep; conversely, there was stronger correlation and agreement for MVPA and LPA on weekend days. Finally, based on Bland-Altman plots, we observed that with increasing MVPA, children tended to report higher MVPA than that measured by the accelerometer. There were no clear trends for the other behaviors., Conclusions: MEDAL may be used to assess the movement behaviors of children. Based on self-reports, the children are able to estimate their time spent in MVPA, inactivity, and night sleep although actual time spent in these behaviors may differ from accelerometer-derived estimates; self-reported LPA warrant cautious interpretation. Observable differences in reporting accuracy exist between weekdays and weekend days., (©Sarah Yi Xuan Tan, Airu Chia, Bee Choo Tai, Padmapriya Natarajan, Claire Marie Jie Lin Goh, Lynette P Shek, Seang Mei Saw, Mary Foong-Fong Chong, Falk Müller-Riemenschneider. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 24.06.2022.)

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., Competing Interests: Disclosures Mark Y. Chan receives speaker fees and research grants from Astra Zeneca, Abbott Technologies, and Boston Scientific. The remaining authors have nothing to disclose. The other authors have no conflict of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer., Patients and Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion., Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index., Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies., (©2022 American Association for Cancer Research.)

Background: Gay, bisexual, and other men who have sex with men (GBMSM) are at disproportionately higher risk of acquiring HIV and other sexually transmitted infections (STI). While HIV/STI testing rates among GBMSM are increasing worldwide, they remain suboptimal in a variety of settings. While many studies have attempted to evaluate the efficacy of a variety of community-based campaigns, including peer and reminder-based interventions on HIV/STI testing, however few have attempted to do so for a web drama series., Objective: This study evaluates the effectiveness of a popular web drama video series developed by a community-based organization in Singapore for GBMSM on HIV and other STI testing behaviors., Methods: The study is a pragmatic, randomized controlled trial to evaluate a popular web drama video series developed by a community-based organization in Singapore for GBMSM. A total of 300 HIV-negative, GBMSM men in Singapore aged 18 to 29 years old were recruited and block-randomized into the intervention (n=150) and control arms (n=150). Primary outcomes included changes in self-reported intention to test for, actual testing for, and regularity of testing for HIV, syphilis, chlamydia or gonorrhea, while secondary outcomes include changes in a variety of other knowledge-based and psychosocial measures at the end of the study period., Results: Overall, 83.3% (125/150) of participants in the intervention arm completed the proof of completion survey, compared to 88.7% (133/150) in the control arm. We found improvements in self-reporting as a regular (at least yearly) tester for HIV (15.9% difference, 95% CI, 3.2% to 28.6%; P=.02), as well as chlamydia or gonorrhea (15.5% difference, 95% CI, 4.2% to 26.9%; P=.009), indicating that the intervention had positively impacted these outcomes compared to the control condition. We also found improvements in participants' intentions to test for HIV (16.6% difference, 95% CI, 4.3% to 28.9%; P=.009), syphilis (14.8% difference, 95% CI, 3.2% to 26.4%; P=.01), as well as chlamydia or gonorrhea (15.4% difference, 95% CI, 4.2% to 26.6%; P=.008), in the next 3 months, indicating that the intervention was effective in positively impacting intention for HIV and other STI testing among participants., Conclusions: There are clear benefits for promoting intentions to test regularly and prospectively on a broad scale through this intervention. This intervention also has potential to reach GBMSM who may not have access to conventional HIV and other STI prevention messaging, which have typically been implemented at sex-on-premises venues, bars, clubs, and in sexual health settings frequented by GBMSM. When coupled with community or population-wide structural interventions, the overall impact on testing will likely be significant., Trial Registration: ClinicalTrials.gov NCT04021953; https://clinicaltrials.gov/ct2/show/NCT04021953., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2019-033855., (©Rayner Kay Jin Tan, Wee Ling Koh, Daniel Le, Sumita Banerjee, Martin Tze-Wei Chio, Roy Kum Wah Chan, Christina Misa Wong, Bee Choo Tai, Mee Lian Wong, Alex R Cook, Mark I-Cheng Chen, Chen Seong Wong. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.05.2022.)

Neurosurgeons today are inundated with rapidly amassing neurosurgical research publications. Systematic reviews and meta-analyses have consequently surged in popularity because, when executed properly, they constitute a high level of evidence and may save busy neurosurgeons many hours of combing and reviewing the literature for relevant articles. Meta-analysis refers to the quantitative (and discretionary) component of systematic reviews. It involves applying statistical techniques to combine effect sizes from multiple studies, which might offer more actionable insights than a systematic review without meta-analysis. Well-executed meta-analyses may prove instructive for clinical practice, but poorly conducted ones sow confusion and have the potential to cause harm. Unfortunately, recent audits have found the conduct and reporting of meta-analyses in neurosurgery (but also other surgical disciplines) to be relatively lackluster in methodologic rigor and compliance to established guidelines. Some of these deficiencies can be easily remedied through better awareness and adherence to prescribed standards-which will be reviewed in this article-but others stem from inherent problems with the source data (e.g., poor reporting of original research) as well as unique constraints faced by surgery as a field (e.g., lack of equipoise for randomized trials, or existence of learning curves for novel surgical procedures, which can lead to temporal heterogeneity), which may require unconventional tools (e.g., cumulative meta-analysis) to address. Therefore, it is also our goal to take stock of the unique issues encountered by surgeons who do meta-analysis and to highlight various techniques-some of which less well-known-to address such challenges., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy ( n  = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.

Background: Bioelectrical impedance analysis (BIA) devices have been advocated to guide volume management in hemodialysis (HD) patients. We hypothesized that understanding the dynamics of fluid shifts in different body segments may provide additional insight on preventive measures to reduce the risk of intradialytic hypotension., Methods: A prospective observational study was conducted among 42 HD patients at risk of hypotension who were admitted as emergencies inpatient., Results: A total of 191 BIA measurements were made during the 42 HD sessions, and hypotension occurred during 52 measurements (27%). The extracellular water (ECW) to intracellular water ratio (EIR) was measured in different body segments and declined significantly only in the non-access arm with increasing HD session duration (β = -0.04; 95% confidence interval (CI): -0.05 to -0.03, p < 0.01). There was no significant association between EIR and hypotension with respect to the different body segments. Only pre-HD N-terminal-pro b-type natriuretic peptide was significantly associated with hypotension (β = 0.20, 95% CI: 0.04 to 0.89, p = 0.04). There was no association between relative blood volume monitoring change and EIR., Conclusion: In summary, we found that segmental BIA during HD was unable to detect or predict hypotension during dialysis. Although BIA is able to provide information about ECW and guide clinical assessment of volume in HD patients prior to dialysis, our findings did not suggest the use of serial measurements of changes in EIR in different body segments during HD provided sufficient information to predict intradialytic hypotension. Similarly, changes in EIR did not provide information on changes in plasma volume that could potentially trigger interventions to prevent or reduce intra-dialytic hypotension., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

There is limited data on the dietary patterns of 5-year-old children in Asia. The study examined childhood dietary patterns and their maternal and child correlates in a multi-ethnic Asian cohort. Based on caregiver-reported 1-month quantitative FFQ of 777 children from the Growing Up in Singapore Towards healthy Outcomes cohort, cluster analysis identified two mutually exclusive clusters. Children in the 'Unhealthy' cluster (43·9 %) consumed more fries, processed meat, biscuits and ice cream, and less fish, fruits and vegetables compared with those in the 'Healthy' cluster (56·1 %). Children with mothers of lower educational attainment had twice the odds of being assigned to the 'Unhealthy' cluster (adjusted OR (95 % CI) = 2·19 (95 % CI 1·49-3·24)). Children of Malay and Indian ethnicities had higher odds of being assigned to the 'Unhealthy' cluster (adjusted OR = 25·46 (95 % CI 15·40, 42·10) and 4·03 (95 % CI 2·68-6·06), respectively), relative to Chinese ethnicity. In conclusion, this study identified two dietary patterns in children, labelled as the 'Unhealthy' and 'Healthy' clusters. Mothers' educational attainment and ethnicity were two correlates that were associated with the children's assignments to the clusters. These findings can assist in informing health promotion programmes targeted at Asian children.

Purpose: Few studies have described adherence to dietary patterns over time in women of childbearing age. This study aims to describe, examine the stability and changes in dietary patterns between pregnancy and 6 years post-pregnancy and the sociodemographic and lifestyle factors influencing the adherence over time., Methods: During pregnancy and at 6 years post-pregnancy, 24-h recalls and food frequency questionnaires were collected, respectively, from 709 women. Data on sociodemographic and lifestyle factors were collected via questionnaires. Dietary patterns were identified using principal component analysis and stability assessed using Pearson's correlation coefficients (r) and Cohen's weighted kappa (κ). Associations with sociodemographic characteristics were assessed by multiple logistic regression., Results: The 'Fruits, Vegetables and Legumes' (FVL) and 'Seafood, Noodle, Soup' (SNS) patterns were identified at both time points, with low correlation for the dietary pattern z scores (r 0.2 and 0.3, respectively) and modest agreement in tertile assignment, suggesting poor stability. An 'unhealthy' pattern was only observed at 6 years post-pregnancy. Women who showed increased adherence to FVL pattern had higher educational attainment and exhibited healthy lifestyle behaviours. Women who had gestational diabetes during pregnancy were less likely to decrease adherence to FVL pattern over time. Women who adhered more closely to the 'unhealthy' pattern at 6 years post-pregnancy tended to be younger, of Malay ethnicity, had lower socioeconomic status, were less physically active and had additional pregnancies., Conclusions: Dietary habits of women became less healthy during the transition from pregnancy to 6 years post-pregnancy. However, results should be interpreted with caution due to the different dietary assessment tools used at the two time points., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Type 2 diabetes mellitus (T2DM) poses huge burden and cost on the healthcare system. Mobile health (mHealth) interventions that incorporate wearables may be able to improve diabetes self-management. The aim of this randomized controlled trial (RCT) is to investigate the clinical and cost-effectiveness of personalized educational and behavioral interventions delivered through an EMPOWER mobile application (app) among patients with T2DM., Methods: This is a parallel two-arm randomized controlled trial (RCT). Patients with T2DM recruited from primary care will be randomly allocated in a 1:1 ratio to either intervention or control group. The intervention group will receive personalized educational and behavioral interventions through the EMPOWER app in addition to their usual clinical care. The control group will receive the usual clinical care for their T2DM but will not have access to the EMPOWER app. Our primary outcome is patient activation score at 12 months. Secondary outcomes will include HbA1c, physical activity level and diet throughout 12 months; quality of life (QoL), medication adherence, direct healthcare cost and indirect healthcare cost at 6 and 12 months., Discussion: This RCT will provide valuable insights into the effectiveness and implementation of personalized educational and behavioral interventions delivered through mobile application in T2DM management. Findings from this study can help to achieve sustainable and cost-effective behavioral change in patients with T2DM, and this can be potentially scaled to other chronic diseases such as hypertension and dyslipidemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kwan, Yoon, Tan, Tai, Tan, Phang, Tan, Tan, Quah, Koot, Teo and Low.)

Current evidence from randomized controlled trials (RCTs) and systematic reviews on the utility of convalescent plasma (CP) in patients with coronavirus disease 2019 (COVID-19) suggests a lack of benefit. We conducted an updated meta-analysis of RCTs with trial sequential analysis to investigate whether convalescent plasma is futile in reducing mortality in patients hospitalized with COVID-19. We searched 6 databases from December 1, 2019 to August 1, 2021 for RCTs comparing the use of CP with standard of care or transfusion of non-CP standard plasma in patients with COVID-19. The risk of bias was assessed using the Cochrane Risk-of-Bias 2 Tool. Random effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the aggregate risk for in-hospital mortality between both arms. We conducted a trial sequential analysis (TSA) based on the pooled relative risks (RRs) for in-hospital mortality. Secondary outcomes included the pooled RR for receipt of mechanical ventilation and mean difference in hospital length of stay. We included 18 RCTs (8702 CP, 7906 control). CP was not associated with a significant mortality benefit (RR: 0.95, 95%-CI: 0.86-1.04, P = .27, high certainty). Subgroup analysis did not find any significant differences (p interaction  = 0.30) between patients who received CP within 8 days of symptom onset (RR: 0.97, 95%-CI: 0.79-1.19, P = .80), or after 8 days (RR: 0.79, 95%-CI: 0.57-1.10, P = .16). TSA based on a RR reduction of 10% from a baseline mortality of 20% found that CP was not effective, with the pooled effect within the boundary for futility. CP did not significantly reduce the requirement for mechanical ventilation (RR: 1.00, 95%-CI: 0.91-1.10, P = .99, moderate certainty) or hospital length of stay (+1.32, 95%-CI: -1.86 to +4.52, P = .42, low certainty). CP does not improve relevant clinical outcomes in patients with COVID-19, especially in severe disease. The pooled effect of mortality was within the boundary of futility, suggesting the lack of benefit of CP in patients hospitalized with COVID-19., (Copyright © 2021. Published by Elsevier Inc.)

Background: Conventional therapy may be inadequate for many patients with axial spondyloarthritis (axSpA). Traditional Chinese medicine (TCM) may be a viable alternative, but its effectiveness for axSpA is unknown. We are currently conducting a pragmatic randomised controlled trial (RCT) to investigate the effectiveness of a TCM collaborative model of care (TCMCMC), which combines usual rheumatologic care with acupuncture for patients with axSpA. This nested qualitative sub-study aims to identify facilitators of and barriers to the implementation of the TCMCMC., Methods: We conducted individual in-depth interviews with participants who had completed the acupuncture regimen to elicit opinions on the facilitators of and barriers to the implementation of the TCMCMC. The interviews were transcribed and analysed using thematic analysis., Results: Twelve participants were included, with data saturation occurring after 10 interviews. The analysis revealed both a number of important 'facilitators' and 'barriers'. Facilitators to the implementation of the TCMCMC included effectiveness of TCM to relieve symptoms, inadequacy of conventional treatment and positive social perceptions of TCM. Barriers included scepticism towards TCM, inability of TCM to provide instant relief, needle-related discomfort, variable effectiveness of TCM influenced by physicians' skills and experience and the high cost of TCM. Recommendations to overcome barriers included further patient education about TCM., Conclusion: Policymakers should take into account the various feasibility factors identified in this study when developing and implementing a TCMCMC., Trial Registration Number: NCT03420404 (ClinicalTrials.gov).

Objective: Laparoscopic appendectomy is a common operation that is frequently performed by junior surgical residents. We investigated the effect of a structured training program on the proficiency of junior residents in acquiring skills necessary in this operation., Design and Participants: This is a randomized pilot trial. Between December 2014 and July 2018, twenty junior residents were recruited for this study. 11 were randomized to receive a structured training program of supervised, task-specific training. Each resident subsequently performed ten cases of laparoscopic appendectomy with their performance assessed for the last 5. The GOALS scale was used as the primary endpoint. Secondary endpoints were perioperative outcomes. The effect of intervention on these outcomes were evaluated assuming a linear mixed effect multi-level model. The study was single-blinded as the assessors did not know which group each resident belonged to., Results: There were no statistically significant differences in the total GOALS score or any of its individual domains. After adjusting for the number of operations done within the trial, the mean difference between the total GOALS score was 0.07 (95% CI -0.76 to 0.90, P=0.866). Blood loss, hospital stay and postoperative complication rates were similar. There was suggestion of a shorter operative time (effect estimate -9.03, 95% CI -19.56 to 1.50) in the intervention arm although statistical significance was not achieved. No avoidable adverse events due to this study were recorded., Conclusion: Structured training program did not significantly improve surgical performance and outcomes in laparoscopic appendectomy in this pilot trial. Despite these findings, residents can still potentially mount their learning curves in laparoscopy earlier in a safe environment with such a program which is especially important in the era of minimally invasive surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since the introduction of the integrated care model, understanding how social interactions and community resources can alleviate caregivers' burden is vital to minimizing negative patients' outcomes. This study ( n = 214) examined the associations between these factors and caregivers' burden in stroke settings. It used 3-month and 1-year post-stroke data collected from five tertiary hospitals. Subjective and objective caregivers' burdens were measured using Zarit burden interview and Oberst caregiving burden scale respectively. The independent variables examined were quality of care relationship, care management strategies for managing patients' behaviour, family caregiving conflict, formal service usage and assistance to the caregiver. Significant associations were determined using mixed effect modified Poisson regressions. For both types of burden, the scores were slightly higher at 3 months as compared to 1 year. Poorer care-relationship (relative risk: 0.81, 95% confidence interval (CI): 0.70-0.94) and adopting positive care management strategies (relative risk: 1.05, 95% CI: 1.02-1.07) were independently associated with a high subjective burden. Providing assistance to caregivers (relative risk: 2.45, 95% CI: 1.72-3.29) and adopting positive care management strategies (relative risk: 1.03, 95% CI: 1.02-1.04) were independently associated with a high objective burden. Adopting positive care management strategies at 3 months had a significant indirect effect (standardised β: 0.11, 95% CI: 0.01 to 0.20) on high objective burden at one year. Healthcare providers should be aware that excessive care management strategies and assistance from family members may add to caregivers' burden.

Background and Aims: Availability of transient elastography (TE) limits the application of Baveno-VI criteria. In a derivation study, the ABP criteria (Albumin >40 g/l, Bilirubin <22 μmol/l and Platelet >114,000/μl) had been shown to perform well in identifying compensated advanced chronic liver disease (cACLD) patients without high-risk varices (HRV). We aim to externally validate this novel ABP criteria for the exclusion of HRVs among cACLD patients., Methods: Data was retrospectively collected from consecutive cACLD patients with paired TE and esophagogastroduodenoscopy (EGD) performed between 2011 and 2017 in Changi General Hospital, Singapore. We estimate the discriminative ability of ABP criteria in validation cohort using AUROC and calibration-in-the-large. We subsequently compare the performance between ABP and Baveno-VI criteria in the validation cohort., Results: Among 314 patients included in our validation cohort, 32 (10.2%) had HRV on screening EGD. Application of ABP criteria within this validation cohort has increased discriminative ability than the derivation cohort. The AUROC of validation and derivation cohort were 0.68 (0.60-0.76) and 0.66 (0.60-0.76), respectively. The mean and standard error for calibration-in-the-large and calibration slope were -0.08 (0.22) and 0.93 (0.26) respectively. The ABP criteria had excellent performance in excluding HRV and will spare more screening EGDs than the Baveno-VI criteria (39.2% vs 27.4%, p < 0.001), without missing more HRVs., Conclusion: We validated the performance of ABP criteria for the exclusion of HRVs in cACLD patients. ABP criteria is superior to Baveno-VI criteria by sparing more screening EGD without the need of TE., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Organ shortage is still a world-wide problem, resulting in long waiting lists for kidney, liver, and heart transplant candidates across many transplant centers globally. This has resulted in the move toward presumed consent to increase deceased organ donation rates. However, there remains a paucity of literature on public attitude and barriers regarding the opt-out system, with existing studies limited to Western nations. Therefore, this study aimed to understand public sentiment and different barriers toward organ donation from the perspective of Singapore, a highly diverse and multiethnic Asian society. Methods: A cross-sectional community semi-structured interview was conducted in a public housing estate in Singapore. Pilot test was undertaken before participants were interviewed face-to-face by trained personnel. All statistical evaluations were conducted using Stata. The χ 2 -test compared subgroups based on patient characteristics while multivariable logistic regression identified predictors of willingness to donate/ assent. Effect estimates were quantified using odds ratio (OR). Findings: Out of 799 individuals, 85% were agreeable to organ donation after death and 81% were willing to assent to donations of family members' organs, which declined by 16% ( p < 0.001) after a clinical scenario was presented. Demographic factors including ethnicity, education, marital, and employment status affected willingness to donate and assent. Knowledge correlated significantly with willingness to donate and assent. In particular, knowledge regarding brain death irreversibility had the strongest correlation (AOR 2.15; 95% CI 1.60-2.89). Conclusions: Organ donation rates remain low albeit presumed consent legislation, due to patient-level barriers, including but not limited to knowledge gaps, cultural values, religious backgrounds, and emotional impact at relatives' death. To effectively boost donor rates, it is crucial for policy makers to invest in public education and improve transplant provisions and family protocols., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Muthiah, Chua, Griva, Low, Lim, Ng, Hwang, Yap, Iyer, Bonney, Anantharaman, Huang, Tan, Lee, Kow and Tai.)

Introduction: Analysis of risk factors can pave the way for reducing unscheduled hospital readmissions and improve resource utilisation., Methods: This was a concurrent nested, mixed method study. Factors associated with patients readmitted within 30 days between 2011 and 2015 at the National University Hospital, Singapore (N=104,496) were examined. Fifty patients were sampled in 2016 to inform an embedded qualitative study. Narrative interviews explored the periods of readmissions and related experiences, contrasted against those of non-readmitted patients., Results: Neoplastic disease (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.70-2.15), number of discharged medications (5 to 10 medications OR 1.21, 95% CI 1.14-1.29; ≥11 medications OR 1.80, 95% CI 1.66-1.95) and length of stay >7 days (OR 1.46, 95% CI 1.36-1.58) were most significantly associated with readmissions. Other factors including number of surgical operations, subvention class, number of emergency department visits in the previous year, hospital bill size, gender, age, Charlson comorbidity index and ethnicity were also independently associated with hospital readmissions. Although readmitted and non-readmitted patients shared some common experiences, they reported different psychological reactions to their illnesses and viewed hospital care differently. Negative emotions, feeling of being left out by the healthcare team and perception of ineffective or inappropriate treatment were expressed by readmitted patients., Conclusion: Patient, hospital and system-related factors were associated with readmissions, which may allow early identification of at-risk patients. Qualitative analysis suggested several areas of improvement in care including greater empowerment and involvement of patients in care and decision making.

Background: The veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients., Methods: Consecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture 'cure' models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time., Results: 318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637-6.003) at 12 months to 2.048 (95% CI: 1.038-4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%-33.6%) and 34.2% (95% CI: 17.4%-50.9%) among patients with left-sided and right-sided primary disease respectively., Conclusion: Primary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)