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Background: Decline in renal function impairs systemic clearance of amyloid-β which characterizes Alzheimer's disease while albuminuria is associated with blood-brain barrier disruption due to endothelial damage. Arterial stiffness adversely affects the brain with high pulsatile flow damaging cerebral micro-vessels., Objective: To examine association between a novel kidney disease index (KDI), which is a composite index of estimated glomerular filtration (eGFR) and urinary albumin-to-creatinine ratio (uACR), and cognitive function with potential mediation by arterial stiffness., Methods: This was a longitudinal multi-center study of participants with type 2 diabetes (T2D) aged 45 years and above. We assessed cognitive function with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Pulse wave velocity (PWV), an index of arterial stiffness, was measured using applanation tonometry method. KDI was calculated as geometric mean of 1/eGFR and natural logarithmically-transformed (ln)(ACR*100)., Results: There were 1,303 participants with mean age 61.3±8.0 years. LnKDI was associated with lower baseline RBANS total score with adjusted coefficient -2.83 (95% CI -4.30 to -1.35; p  < 0.001). 590 participants were followed over up to 8.6 years. LnKDI was associated with lower follow-up RBANS score in total, immediate memory, visuo-spatial/construction and attention domains with corresponding adjusted coefficients -2.35 (95% CI -4.50 to -0.20; p  = 0.032), -2.93 (95% CI -5.84 to -0.02; p  = 0.049), -3.26 (95% CI -6.25 to -0.27; p  = 0.033) and -4.88 (95% CI -7.95 to -1.82; p  = 0.002). PWV accounted for 19.5% of association between and follow-up RBANS total score., Conclusions: KDI was associated with lower cognitive function globally, and in immediate memory, visuo-spatial/construction and attention domains. Arterial stiffness mediated the association between KDI and cognitive decline in patients with T2D., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Background: The misuse and overuse of antibiotics accelerate the development of antimicrobial resistance (AMR). Serious games, any form of games that serve a greater purpose other than entertainment, could augment public education above ongoing health promotion efforts. Hence, we developed an evidence-based educational serious game app-SteWARdS Antibiotic Defence-to educate players on good antibiotic use practices and AMR through a game quest comprising 3 minigames and interaction with the nonplayer characters., Objective: We aimed to evaluate the effectiveness of the SteWARdS Antibiotic Defence app in improving the knowledge of, attitude toward, and perceptions (KAP) of appropriate antibiotic use and AMR among the public in Singapore., Methods: We conducted a 2-arm parallel randomized controlled trial, recruiting visitors aged 18-65 years from 2 polyclinics in Singapore. Intervention group participants had to download the SteWARdS Antibiotic Defence app (available only in English and on the Android platform) on their smartphones and complete the quest in the app. Participants took half a day to 2 weeks to complete the quest. The control group received no intervention. Knowledge questions on antibiotic use and AMR (11 binary questions) were self-administered at baseline, immediately after the intervention, and 6-10 weeks post intervention, while attitudes and perception questions (14 three-point Likert-scale questions) were self-administered at baseline and 6-10 weeks post intervention. We also collected participants' feedback on app usage., Results: Participants (n=348; intervention: n=142, control: n=206) had a mean age of 36.9 years. Intervention group participants showed a statistically significant improvement in mean knowledge score (effect size: 0.58 [95% CI 0.28-0.87]) compared with controls after accounting for age, educational level, and exposure to advertisements on antibiotics and AMR. Intervention participants also showed a statistically significant improvement in mean attitude-perception scores (effect size: 0.98 (95% CI 0.44-1.52)) after adjusting for marital status and race. A majority of participants agreed that the "SteWARdS Antibiotic Defence" app improved their awareness on antibiotic use (135/142, 95.1%) and AMR (136/142, 95.8%). About 73.9% (105/142) of the participants agreed that the app is easy to use, 70.4% (100/142) agreed that the app was enjoyable, and 85.2% (121/142) would recommend the app to others., Conclusions: Our educational serious game app improves participants' KAP on appropriate antibiotic use and AMR. Public education apps should be engaging, educational, easy to use, and have an attractive user interface. Future research should assess the effectiveness of interventions in facilitating long-term knowledge retention and long-lasting behavioral change., Trial Registration: ClinicalTrials.gov NCT05445414; https://clinicaltrials.gov/ct2/show/NCT05445414., International Registered Report Identifier (irrid): RR2-10.2196/45833., (©Zhilian Huang, Jing Teng Ow, Wern Ee Tang, Angela Chow. Originally published in JMIR Serious Games (https://games.jmir.org), 05.09.2024.)

Context: Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear., Objective: Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator., Methods: T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function., Results: Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95% CI -2.55 to -.21; P = .021) and -1.38 (95% CI -2.70 to -.07; P = .039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95% CI -14.14 to -.74; P = .030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score., Conclusion: Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clinicians' information-seeking behaviours impact patient care quality. Earlier studies indicated that barriers to accessing information deter clinicians from seeking answers to clinical questions., Objectives: To explore primary care clinicians' information-seeking behaviour at point-of-care, focusing on when and how they seek answers to clinical questions., Methods: Semi-structured interviews were conducted with 45 clinicians after clinical sessions to investigate their information-seeking habits. Follow-up interviews were conducted after a week for those intending to address unanswered queries., Results: Two thirds of clinicians encountered questions during care, with nearly three quarters resolving them during the session. Colleagues, guidelines and online platforms were common information sources, with smartphones being used to access Google, WhatsApp or UpToDate®. Facilitators included reliable sources and the drive to confirm knowledge, while barriers included ineffective search methods and high workload. Despite challenges, most clinicians expressed satisfaction with their information-seeking process., Discussion: The findings underscore the increasing use of smartphones for accessing clinical information among Singaporean primary care clinicians and suggest the need for tailored training programmes and guidelines to optimise information-seeking practices., Conclusion: Insights from this study can inform the development of training programmes and guidelines aimed at improving information-seeking practices among primary care clinicians, potentially enhancing patient care quality., (© 2024 The Authors Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.)

Background: The growth of medical knowledge and patient care complexity calls for improved clinician access to evidence-based resources. This study aimed to explore the primary care clinicians' preferences for, barriers to, and facilitators of information-seeking in clinical practice in Singapore., Methods: A convenience sample of ten doctors and ten nurses was recruited. We conducted semi-structured face-to-face in-depth interviews. The interviews were recorded, transcribed verbatim, and analysed using thematic content analysis., Results: Of the 20 participants, eight doctors and ten nurses worked at government-funded polyclinics and two doctors worked in private practice. Most clinicians sought clinical information daily at the point-of-care. The most searched-for information by clinicians in practice was less common conditions. Clinicians preferred evidence-based resources such as clinical practice guidelines and UpToDate®. Clinical practice guidelines were mostly used when they were updated or based on memory. Clinicians also commonly sought answers from their peers. Furthermore, clinicians frequently use smartphones to access the Google search engine and UpToDate® app. The barriers to accessing clinical information included the lack of time, internet surfing separation of work computers, limited search functions in the organisation's server, and limited access to medical literature databases. The facilitators of accessing clinical information included convenience, easy access, and trustworthiness of information sources., Conclusion: Most primary care clinicians in our study sought clinical information at the point-of-care daily and reported increasing use of smartphones for information-seeking. Future research focusing on interventions to improve access to credible clinical information for primary care clinicians at the point-of-care is recommended., Trial Registration: This study has been reviewed by NHG Domain Specific Review Board (NHG DSRB) (the central ethics committee) for ethics approval. NHG DSRB Reference Number: 2018/01355 (31/07/2019)., (© 2024. The Author(s).)

Introduction: Anxiety and depressive disorders are highly prevalent mental health conditions worldwide. However, little is known about their specific prevalence in primary care settings. This study aimed to determine the prevalence of depression and anxiety in the primary care population and identify associated patient characteristics., Method: We conducted a cross-sectional study using stratified sampling by age with a self-administered questionnaire survey in Singapore's National Health-care Group Polyclinics from December 2021 to April 2022. A total score of Patient Health Questionnaire-9 (PHQ-9) ≥10 represents clinical depression, and a total score of Generalised Anxiety Disorder-7 (GAD-7) ≥10 indicates clinical anxiety. Multivariable logistic regression was used to identify the factors associated with depression and anxiety., Results: A total of 5694 patients were approached and 3505 consented to the study (response rate=61.6%). There was a higher prevalence of coexisting clinical depression and anxiety (DA) (prevalence=5.4%) compared to clinical depression only (3.3%) and clinical anxiety only (1.9%). The odds of having DA were higher among those aged 21-39 years (odds ratio [OR] 13.49; 95% confidence interval [CI] 5.41-33.64) and 40-64 years (OR 2.28; 95% CI 1.03-5.03) compared to those ≥65 years. Women had higher odds of having DA (OR 2.33; 95% CI 1.54-3.50) compared to men. Respondents with diabetes had higher odds of having DA (OR 1.78; 95% CI 1.07-2.94) compared to those without diabetes., Conclusion: Coexisting clinical depression and anxiety are significantly present in the primary care setting, especially among younger individuals, patients with diabetes and women. Mental health screening programmes should include screening for both depression and anxiety, and target these at-risk groups., Competing Interests: The authors have no conflict of interest to declare.

Objectives: To understand the lived experience of adults with overweight/obesity and early type 2 diabetes in a modern urban environment, and the interrelations among the various aspects of these experiences and participants' attitudes to weight management., Design: Qualitative inductive approach to analysing data thematically from semistructured interviews and interpreted from a socioecological perspective., Setting: Primary care clinics located in northern and central Singapore., Participants: 21 patients between 29 and 59 years old who are living with overweight/obese (Body Mass Index of 25.3-44.0kg/m 2 ) and type 2 diabetes for 6 years or less., Results: The main themes - everyday life, people around me and within me - pointed to a combination of barriers to weight and health management for participants. These included environmental factors such as easy physical and digital access to unhealthy food, and high-stress work environments; social factors such as ambiguous family support and dietary practices of peers; and individual factors such as challenges with self-regulation, prioritising work, dealing with co-existing medical conditions and the emotional significance of food. While lack of motivation and cultural dietary practices are hard to change, a problem-solving attitude, and presence of role models, may enable behaviour change., Conclusion: An exploration of the lifeworld of patients with overweight/obese and early type 2 diabetes revealed that work demands, dietary practices in the workplace and at home, and the easy availability of calorie-dense foods afforded by a technology-infused environment hindered the individual's efforts at maintaining a healthy weight and lifestyle. Policy and initiatives promoting work-life balance as well as individualised interventions can support participants' stress management, and problem-solving capability for behaviour change. These barriers stemmed from the various domains of the environmental, interpersonal and intrapersonal but were interrelated. They underscored the need for an integrated approach to weight and diabetes management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Skeletal muscle mass to visceral fat area ratio (SVR) has been recognised as an index of sarcopenic obesity. SVR is associated with type 2 diabetes mellitus (T2DM), metabolic syndrome and arterial stiffness which are known risk factors for cognitive dysfunction. We aimed to investigate association between SVR and cognitive function in patients with T2DM., Methods: This was a cross-sectional study of 1326 patients with T2DM and mean age 61.3 ± 8.0 years. SVR was assessed based on bioelectrical impedance measurements of muscle mass and visceral fat area (VFA). Cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Linear regression was used to examine the association between SVR in quartiles and RBANS score, adjusting for demographics, education, presence of depressive symptoms, clinical covariates and medications., Results: The lower SVR quartiles were negatively associated with RBANS total score in the unadjusted analysis. The corresponding coefficients for Quartiles 1 and 2 SVR were -3.79 (95 % CI -5.39 to -2.19; p < 0.001) and -1.47 (95 % CI -2.86 to -0.07; p = 0.039) in fully adjusted analysis. The negative association between Quartile 1 SVR and RBANS score was evident in immediate memory, delayed memory, visuo-spatial construction, language and attention domains. Muscle mass and VFA alone had weaker associations with RBANS scores., Conclusion: Our study demonstrated, for the first time, an independent association between reduced SVR and lower cognitive function. This is evident in global and multiple cognitive domains. The synergistic effects of reduced muscle mass and visceral obesity may be more pronounced than their independent effects on cognitive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Technology to enhance hypertension management is increasingly used in primary care; however, it has not been evaluated in an Asian primary care setting. We aimed to understand the clinical impact and cost-effectiveness of a technology-enabled home blood pressure monitor when deployed in primary care, and patients' perspectives about the technology., Methods: A quasi-experimental cohort study was conducted in a polyclinic in Singapore. In total, 120 patients with hypertension were assigned to the telemonitoring intervention group. Patients received a home blood pressure device connected to the clinical care team's dashboard through a mobile gateway. Tele-consultations and nurse-led tele-support were carried out using established clinical protocols. In total, 120 patients assigned to the control group continued to receive usual care in the polyclinic. Clinical outcomes, cost-effectiveness, and patient satisfaction were measured 6 months after recruitment., Results: In total, 217 patients completed 6 months of follow-up. Telemonitoring intervention patients had significantly increased odds of having controlled blood pressure by a factor of 2.69 ( p  = 0.01), with the greatest improvement in those whose blood pressure was uncontrolled at baseline ( p  < 0.05). The incremental cost-effectiveness ratios for all patients was S$23,935.14/quality-adjusted life year (<1 gross domestic product per capita), which was very cost-effective based on World Health Organization cost-effectiveness thresholds. There was greater satisfaction in telemonitoring intervention group relating to the convenience of recording and sharing blood pressure measurements with the health care team, consultation advice received, understanding by the health care team of their condition, and were more motivated to monitor their blood pressure., Discussion: Telemonitoring with tele-consultation improved blood pressure control and was more cost-effective than usual care. Patients receiving telemonitoring intervention were also more motivated and satisfied with their care., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The Singapore Study of Macro-Angiopathy and microvascular Reactivity in Type 2 Diabetes (SMART2D) is a prospective cohort study which was started in 2011 to investigate the effect of risk factors on vascular function and diabetes-related complications in Asians. We aimed to compare the longitudinal change in risk factors by accounting for batch effect and assess the tracking stability of risk factors over time in patients recruited for SMART2D. In this study, we (1) described batch effect and its extent across a heterogenous range of longitudinal data parameters; (2) mitigated batch effect through statistical approach; and (3) assessed the tracking stability of the risk factors over time., Methods: A total of 2258 patients with type 2 diabetes mellitus (T2DM) were recruited at baseline. The study adopted a three-wave longitudinal design with intervals of 3 years between consecutive waves. The changes in a few selected risk factors were assessed after calibration, assuming patients with similar demographic and anthropometry profile had similar physiology. The tracking pattern of the risk factors was determined with stability coefficients derived from generalised estimating equations., Results: The medians of the longitudinal differences in risk factors between the waves were mostly modest at <10%. Larger increases in augmentation index (AI), aortic systolic blood pressure (BP) and aortic mean BP were consistently observed after calibration. The medians of the longitudinal differences in AI, aortic systolic BP and aortic mean BP between the waves were <2% before calibration, but increased slightly to <5% after calibration. Most of the risk factors had moderate to high tracking stability. Muscle mass and serum creatinine were among those with relatively high tracking stability., Conclusions: The longitudinal differences in parameters between the waves were overall modest after calibration, suggesting that calibration may attenuate longitudinal differences inflated by non-biological factors such as systematic drift due to batch effect. Changes of the hemodynamic parameters are robust over time and not entirely attributable to age. Our study also demonstrated moderate to high tracking stability for most of the parameters., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Health literacy (HL) is an important determinant of health. Sub-optimal HL can have profound consequences for individuals and health systems. However, little is known about the HL of older Singaporeans., Objective: This study determined the prevalence, socio-demographic and health-related correlates of limited and marginal HL among older Singaporeans (≥65 years)., Methods: Data from a national survey were analysed (n = 2327). HL was measured using the 4-item BRIEF with a 5-point response scale (range 4-20), and classified as limited, marginal, and adequate. Multinomial logistic regression models were applied to identify correlates of limited and marginal HL versus adequate HL., Results: The weighted prevalence of limited HL was 42.0%, marginal HL was 20.4% and adequate HL was 37.7%. In adjusted regression analysis, older adults in advanced age groups with lower education and those living in 1-3 room flats had higher risk of limited HL. Furthermore, having ≥3 chronic diseases (Relative Risk Ratio [RRR] = 1.70, 95% Confidence Interval [95% CI] = 1.15, 2.52), poor self-rated health (RRR = 2.07, 95% CI = 1.56, 2.77), vision impairment (RRR = 2.08, 95% CI = 1.55, 2.80), hearing impairment (RRR = 1.57, 95% CI = 1.15, 2.14) and mild cognitive impairment (RRR = 4.87, 95% CI = 2.12, 11.19) were also associated with limited HL. The likelihood of marginal HL was higher among those with lower education, ≥2 chronic diseases, poor self-rated health (RRR = 1.48, 95% CI = 1.09, 2.00), vision impairment (RRR = 1.45, 95% CI = 1.06, 1.99) and hearing impairment (RRR = 1.50, 95% CI = 1.08, 2.08)., Conclusions: Over two-thirds of older adults faced difficulties in reading, understanding, exchanging, and using health information and resources. There is a pressing need to create awareness about the issues that could result from the mismatch between healthcare system demands and the HL of older adults., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1)., Methods: T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category., Results: Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m 2 ) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression., Conclusions: Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Introduction: Phase angle (PhA), derived from bioelectrical impedance analysis (BIA), is the angle of vector determined by the body's resistance and reactance. It indicates cellular integrity and hydration status. Though extracellular volume excess was associated with chronic kidney disease (CKD) progression, the association between PhA and CKD progression is unknown. Matrix metalloproteinase-2 (MMP-2) is a member of zinc-dependent endopeptidase family and promotes renal interstitial fibrosis. We investigated association between PhA and CKD progression, and whether the association was through MMP-2 in patients with type 2 diabetes mellitus (T2DM)., Method: We conducted a prospective study on 1,078 patients with T2DM (mean age 58.9±9.1 years). PhA was measured using BIA. CKD progression was defined as ≥25% decrease in estimated glomerular filtration rate (eGFR) from baseline with deterioration across eGFR categories. Multiplex immunoassay was used to quantitate MMP-2. We examined association between PhA and CKD progression using Cox proportional hazards model, adjusting for demographics, clinical parameters and medications., Results: Over 8.6 years of follow-up, 43.7% of participants had CKD progression. Compared to tertile 3 PhA (higher level), tertiles 1 and 2 PhA were associated with higher hazards of CKD progression, with corresponding unadjusted hazard ratios (HRs) of 2.27 (95% confidence interval [CI] 1.80-2.87, P<0.001) and 1.57 (95% CI 1.24-2.01, P<0.001). The positive association between tertiles 1 and 2 PhA with CKD progression persisted in the fully adjusted model with corresponding HRs of 1.71 (95% CI 1.30-2.26, P<0.001) and 1.46 (95% CI 1.13-1.88, P=0.004). MMP-2 accounted for 14.7% of association between tertile 1 PhA and CKD progression., Conclusion: Our findings revealed a previously unobserved association between BIA-derived lower PhA and CKD progression through MMP-2 in patients with T2DM.

Background: The misuse and overuse of antibiotics contribute to the acceleration of antimicrobial resistance (AMR), but public knowledge on appropriate antibiotic use and AMR remained low despite ongoing health promotion efforts. App gamification has gained traction in recent years for health promotion and to affect change in health behaviors. Hence, we developed an evidence-based serious game app "SteWARdS Antibiotic Defence" to educate the public on appropriate antibiotic use and AMR and address knowledge gaps., Objective: We aim to evaluate the effectiveness of the "SteWARdS Antibiotic Defence" app in improving the knowledge of, attitude toward, and perception (KAP) of appropriate antibiotic use and AMR among the public. The primary objective is to assess the changes in KAP of antibiotic use and AMR in our participants, while the secondary objectives are to assess the extent of user engagement with the app and the level of user satisfaction in using the app., Methods: Our study is a parallel 2-armed randomized controlled trial with a 1:1 allocation. We plan to recruit 400 participants (patients or their caregivers) aged 18-65 years from government-funded primary care clinics in Singapore. Participants are randomized in blocks of 4 and into the intervention or control group. Participants in the intervention group are required to download the "SteWARdS Antibiotic Defence" app on their smartphones and complete a game quest within 2 weeks. Users will learn about appropriate antibiotic use and effective methods to recover from uncomplicated upper respiratory tract infections by interacting with the nonplayer characters and playing 3 minigames in the app. The control group will not receive any intervention., Results: The primary study outcome is the change in participants' KAP toward antibiotic use and AMR 6-10 weeks post intervention or 6-10 weeks from baseline for the control group (web-based survey). We will also assess the knowledge level of participants immediately after the participant completes the game quest (in the app). The secondary study outcomes are the user engagement level (tracked by the app) and satisfaction level of playing the game (via the immediate postgame survey). The satisfaction survey will also collect participants' feedback on the game app., Conclusions: Our proposed study provides a unique opportunity to assess the effectiveness of a serious game app in public health education. We anticipate possible ceiling effects and selection bias in our study and have planned to perform subgroup analyses to adjust for confounding factors. The app intervention will benefit a larger population if it is proven to be effective and acceptable to users., Trial Registration: ClinicalTrials.gov NCT05445414; https://clinicaltrials.gov/ct2/show/NCT05445414., International Registered Report Identifier (irrid): DERR1-10.2196/45833., (©Zhilian Huang, Wern Ee Tang, Huiling Guo, Karthiga Natarajan, Tau Hong Lee, Tsin Wen Yeo, Angela Chow. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.03.2023.)

Background: Telemedicine is becoming integral in primary care hypertension management, and is associated with improved blood pressure control, self-management and cost-effectiveness. This study explored the experiences of patients and healthcare professionals and their perceived barriers and facilitators in implementing and using a technology-enabled blood pressure monitoring intervention with teleconsultation in the Singapore primary care setting., Methods: This was a qualitative study embedded within the Primary Technology-Enhanced Care Hypertension pilot trial. Patients were selected purposively and invited to participate by telephone; healthcare professionals involved in the trial were invited to participate by email. Individual semi-structured interviews were conducted in English or Mandarin with thirteen patients and eight healthcare professionals. Each interview was audio-recorded and transcribed verbatim. Data were analyzed inductively to identify emergent themes which were then grouped into the dimensions of the socio-technical systems model to study the interactions between the technical, individual and organizational factors involved in the process., Results: Several emergent themes were identified. The factors involved in the implementation and use of the intervention are complex and interdependent. Patients and healthcare professionals liked the convenience resulting from the intervention and saw an improvement in the patient-provider relationship. Patients appreciated that the intervention helped form a habit of regular blood pressure monitoring, improved their self-management, and provided reassurance that they were being monitored by the care team. Healthcare professionals found that the intervention helped to manage workload by freeing up time for other urgent matters. Nevertheless, participants highlighted challenges with usability of the equipment and management portal, data access, and some expressed technology anxiety. Participants suggested patient segmentation for the intervention to be more targeted, wished for a more user-friendly equipment and proposed allocating more resources to the intervention., Conclusions: The implementation and use of telemedicine for hypertension management can engender various benefits and challenges to patients, healthcare professionals and the healthcare system. Stakeholder feedback gathered on the sociotechnical aspects of the technology should be taken into consideration to guide the design, implementation and evaluation of future telemedicine interventions in primary care., Trial Registration: This study was registered on ClinicalTrials.gov on October 9, 2018. ID: NCT03698890., (© 2023. The Author(s).)

Objective: Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-β (TGF-β)-induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes., Research Design and Methods: A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses., Results: During a median follow-up of 8.6 (interquartile range 5.8-9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04-3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19-1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD., Conclusions: Urine LRG1, a TGF-β signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression., (© 2023 by the American Diabetes Association.)

Background: Prescription medication labels (PMLs) predominantly dispensed in English, are an important adjunct to medication counselling. PMLs are routinely used by pharmacy staff to counsel older adults about their medications. This study sought to identify challenges that pharmacy staff observe older adults face in using their PMLs, and to identify and quantify solutions employed by pharmacy staff during medication counselling to address such challenges., Methods: Ten in-depth interviews were done with primary care pharmacy staff to gather the range of challenges and solutions. Subsequently, a quantitative survey, informed by the qualitative findings, was administered to 121 pharmacy staff to assess if the reported solutions were commonly used., Results: The two main challenges were incongruity between PML language (English) and older adults' language proficiency, and poor PML legibility. The solutions, classified under three themes, were simplifying medication information on PMLs, supplementing PMLs with additional medication information and mitigating poor readability., Conclusions: Pharmacy staff observed challenges faced by older adults in using PMLs during medication counselling. Ad-hoc improvisations by pharmacy staff to PMLs were pervasive. System-level PML improvements, such as provision of legible bilingual medication instructions, pharmaceutical pictograms and additional medication information, through patient information leaflets or using quick response (QR) codes on PMLs, should be considered. This will facilitate patient-provider communication, especially in settings with language dissonance between PMLs and patients., Competing Interests: 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., (© 2023 The Authors.)

Background: Trust is of fundamental importance to the adoption of technologies in health care. The increasing use of telemedicine worldwide makes it important to consider user views and experiences. In particular, we ask how the mediation of a technological platform alters the trust relationship between patient and health care provider., Objective: To date, few qualitative studies have focused on trust in the use of remote health care technologies. This study examined the perspectives of patients and clinical staff who participated in a remote blood pressure monitoring program, focusing on their experiences of trust and uncertainty in the use of technology and how this telehealth intervention may have affected the patient-provider relationship., Methods: A secondary qualitative analysis using inductive thematic analysis was conducted on interview data from 13 patients and 8 staff members who participated in a remote blood pressure monitoring program to elicit themes related to trust., Results: In total, 4 themes were elicited that showed increased trust (patients felt reassured, patients trusted the telehealth program, staff felt that the data were trustworthy, and a better patient-provider partnership based on the mutually trusted data), and 4 themes were elicited that reflected decreased trust (patients' distrust of technology, clinicians' concerns about the limitations of technologically mediated interactions, experiences of uncertainty, and institutional risk)., Conclusions: Managing trust relationships plays an important role in the successful implementation of telemedicine. Ensuring that trust building is incorporated in the design of telehealth interventions can contribute to improved effectiveness and quality of care., (©Evelyn Chew, Sok Huang Teo, Wern Ee Tang, David Wei Liang Ng, Gerald Choon Huat Koh, Valerie Hui Ying Teo. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 05.01.2023.)

Aims/hypothesis: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks., Methods: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis., Results: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression., Conclusions/interpretation: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine., (© 2022. The Author(s).)

Aims: To examine the longitudinal association between skeletal muscle mass (SMM) loss and cognitive decline over time in type 2 diabetes mellitus (T2DM)., Methods: We conducted a prospective cohort study of 453 patients from SMART2D cohort with follow-up intervals of 1.6 to 6.4 years. Baseline and follow-up measurements included bio-impedance analysis (BIA) measure of skeletal muscle mass index (SMI) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measure of cognitive function. We examined the association between annual rate of SMI and RBANS scores using linear regression, adjusting for demographics, education, depression, clinical co-variables and presence of apolipoprotein E4 (APOE) Ɛ 4 allele., Results: The mean age of participants was 60.3 ± 7.4 years. Compared to patients with Tertile 1 SMI change, the group with greater SMI decline (Tertile 3 SMI change) experienced 0.30 decline in RBANS total score (95%CI -0.57 to -0.03; p = 0.030) in the adjusted analysis. RBANS scores for subdomains in immediate memory and visuo-spatial/construction were lower in Tertile 3 SMI change group with corresponding coefficients -0.54 (95%CI -1.01 to -0.06; p = 0.026), and -0.71 (95%CI -1.30 to -0.12; p = 0.019) respectively., Conclusion: In patients with T2DM, BIA measure of muscle mass loss over time was independently associated with cognitive decline globally and in the domains of memory and visuo-spatial/construction., Competing Interests: Declaration of competing interest The authors report no potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic wounds commonly decrease patients' quality of life. Understanding how chronic wounds impact a patient's health-related quality of life (HRQoL) is important for healthcare service delivery and treatment management. This study explored HRQoL among patients suffering from chronic wounds and investigated associations with patients' socio-demographics and wound characteristics. Two hundred and thirty-three patients across six primary care clinics were assessed and responded to a survey that collected information on socio-demographic, wound characteristics, and HRQoL using the EQ-5D-5L instrument. Data were analysed by descriptive statistics and generalised linear models. The mean age of patients was 61.2 (SD: 14.6) years; 68.2% were males; and 61.8% were of Chinese origin. Arterial ulcers had the greatest negative impact on HRQoL related to mobility, self-care, pain/discomfort and anxiety/depression, and the lowest VAS mean score 62.31 (SD: 28.3; range: 0-100) indicating the worst health. HRQoL related to mobility was significantly associated with age (β = 0.008, P < .001), non-Chinese ethnicity (β = 0.25, P = .001), mixed ulcers (β = -0.41, P = .022), atypical hard-to-heal wounds (β = -0.38, P = .021), wounds with low (β = 0.24, P = .044) to moderate (β = 0.29, P = .018) exudate level, and a wound duration ≥6 months (β = 0.19, P = .033). The findings can be used to improve healthcare delivery for patients with chronic wound to optimise their HRQoL., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: The rising prevalence of food allergy reported in the United States, UK, and Australia may be attributable to the rise in peanut allergy prevalence. The food allergy prevalence in other parts of the world such as Asia is, however, less well documented., Objective: This study aimed to evaluate the prevalence of cow's milk, egg, and peanut allergies in a general population of Singaporean children below 30 months of age., Methods: A total of 4,115 children from the general population who attended well-baby visits between 2011 and 2015 completed standardized questionnaires to elicit a convincing history of food allergy to estimate the population prevalence of food allergies., Results: The prevalence of a convincing history of cow's milk allergy was 0.51% (95% confidence interval [CI], 0.3-0.7), hen's egg allergy 1.43% (95% CI, 1.1-1.8), and peanut allergy 0.27% (95% CI, 0.12-0.42). Of the 15 of 59 children with a convincing history of hen's egg allergy who consented, 12 (80%) had corroborative positive skin prick tests., Conclusion: The prevalence of food allergy, in particular peanut allergy, in children below 2 years of age is lower in this South East Asian population than reported in Western cohorts. Further research should focus on deciphering differential risk factors for food allergy across different geographical locations., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2022. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Aims: Type 2 diabetes mellitus (T2DM) has been shown to be associated with cognitive decline and dementia. As earlier onset of diabetes implies a longer disease duration and an increased risk to complications, we sought to investigate the effect of T2DM onset on cognitive function of our patients., Methods: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to T2DM patients aged 45-85 from our SMART2D cohort. We assessed the association of the T2DM onset age (both continuous and stratified into 3 groups: early-onset ≤40 (n = 326), middle-aged onset 41-64 (n = 703) and late-onset ≥65 years old (n = 38)) and RBANS cognitive indices in 1067 patients. Potential mediation of this association by vascular compliance using mediation analysis was investigated., Results: T2DM onset associates significantly with RBANS total score. Patients with early T2DM onset have lower RBANS total score as compared to patients with middle-aged onset (β = -2.01, p = 0.0102) and those with late-onset (β = -5.80, p = 0.005). This association was partially mediated by pulse pressure index (25.8%), with indirect effect of 0.028 (Bootstrapped-CI: 0.008-0.047)., Conclusions: Association of early-onset T2DM with cognitive impairment is partly mediated by diminished vascular compliance. Appropriate screening and assessment of cognitive function is important for early intervention and management of cognitive impairment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Triglyceride-glucose (TyG) index is a surrogate marker of insulin resistance. Its role in chronic kidney disease (CKD) progression in Type 2 Diabetes Mellitus (T2DM) is unclear. We investigated the association between TyG index and CKD progression, and possible mediation of the association by pigment epithelium-derived factor (PEDF)., Methods: This was a prospective study on 1571 patients with T2DM. CKD progression was defined as worsening across KDIGO estimated glomerular filtration rate (eGFR) categories with ≥25% reduction from baseline. PEDF was quantitated using enzyme-linked immunosorbent assay method. Cox proportional hazards regression model was used to assess the relationship between TyG index and CKD progression., Results: Over a follow-up period of up to 8.6 years (median 4.6 years, IQR 3.0-3.6), 42.7% of subjects had CKD progression. Every unit increase in TyG was associated with hazards of 1.44 (95%CI 1.29-1.61; p < 0.001) in unadjusted analysis and 1.21 (1.06-1.37; p = 0.004) in fully adjusted model. Compared to tertile 1, tertiles 2 and 3 TyG index were positively associated with CKD progression with corresponding hazard ratios HRs 1.24 (1.01-1.52; p = 0.037) and 1.37 (1.11-1.68; p = 0.003) in fully adjusted models. PEDF accounted for 36.0% of relationship between TyG index and CKD progression., Conclusions: Higher TyG index independently predicted CKD progression in T2DM. PEDF mediated the association between TyG index and CKD progression.

Context: Observational studies have shown that elevated uric acid (UA) is associated with chronic kidney disease (CKD). However, whether the relationship is causal remains unclear., Objective: To determine the association of plasma UA and incident CKD and the causal relationship between plasma UA and rapid decline in kidney function (RDKF) in patients with type 2 diabetes (T2D)., Methods: Multivariable Cox regression was conducted to evaluate the hazard ratio (HR) between plasma UA and incident CKD among 1300 normoalbuminuric patients in 2 T2D study cohorts (DN, n = 402; SMART2D, n = 898). A weighted genetic risk score (wGRS) was calculated based on 10 single nucleotide polymorphism (SNPs) identified in genome-wide association studies of UA in East Asians. Mendelian randomization (MR) analysis was performed among 1146 Chinese T2D patients without CKD (estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73m2) at baseline (DN, 478; SMART2D, 668). The wGRS and individual SNPs were used as genetic instruments and RDKF was defined as eGFR decline of 5 mL/min/1.73m2/year or greater., Results: During mean follow-up of 5.2 and 5.4 years, 81 (9%) and 46 (11%) participants in SMART2D and DN developed CKD, respectively. A 1-SD increment in plasma UA conferred higher risk of incident CKD (DN, adjusted-HR = 1.40 [95% CI, 1.02-1.91], P = 0.036; SMART2D, adjusted-HR = 1.31 [95% CI, 1.04-1.64], P = 0.018). Higher wGRS was associated with increased odds for RDKF (meta-adjusted odds ratio = 1.12 [95% CI, 1.01-1.24], P = 0.030, Phet = 0.606)., Conclusion: Elevated plasma UA is an independent risk factor for incident CKD. Furthermore, plasma UA potentially has a causal role in early eGFR loss in T2D patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Asthma is a significant health issue in primary care. We examined the journeys of patients with asthma exacerbations requiring urgent therapy at a primary care clinic in Singapore., Methods: Face-to-face semi-structured interviews were conducted with patients who received urgent therapy for asthma exacerbation at a primary care clinic. Data collected was used to construct themes., Results: Fifteen multi-ethnic adult patients were recruited. Participants cited treatment cost, underuse of preventer medication, difficulties attending routine asthma care due to work, and stigma as barriers to asthma control. Reasons for delay in seeking urgent care for asthma were: inability to access medical care out of hours, competing priorities, perception that an exacerbation was 'not serious enough', difficulty recognizing symptoms of asthma exacerbation, and being tired or despondent. Participants were triggered to seek care due to failure of reliever inhalers, duration of symptoms, sleep disturbance, inability to work, or advice from others. During an exacerbation, participants often initiated other self-management measures besides using reliever medication. This included over-the-counter medications and non-pharmacological interventions (e.g. drinking water). Of the 15 patients interviewed, only one stepped up preventer inhaler adequately, according to their Asthma Action Plan (AAP)., Conclusions: In caring for patients with asthma, primary care providers should address patients' asthma self-management skills, such as recognizing symptoms of asthma exacerbations and regular preventer use, and provide clear instructions on how to respond to asthma symptoms (AAP). Minimizing direct (medication and consultation fees) and indirect costs (loss of earnings and adverse impact on employment prospects) are also important considerations., (© 2022. The Author(s).)

We have noted the views expressed by the authors of the article "The Missed Opportunity of Patient-Centered Medical Homes (PCMH) to Thrive in an Asian Context" by Surendran et al. [...].

Objective: Pictograms on prescription medication labels enhance medication literacy and medication adherence. However, pictograms need to be contextually validated. We assessed the validity of 52 International Pharmaceutical Federation pictograms among 250 older Singaporeans with limited English proficiency., Methods: Participants were randomly assigned 11 pictograms each. For each pictogram, participants were first asked its intended meaning. Then, they were told the intended meaning and asked to rate how well the pictogram represented the meaning, on a scale of 1-7. Pictograms were classified as valid (≥66% participants assigned the pictogram interpreted its intended meaning correctly [transparency criterion] and ≥85% participants rated its representativeness as ≥5 [translucency criterion]), partially valid (only transparency criterion was fulfilled) or not valid. Open-ended questions gathered feedback to improve pictograms., Results: 14 pictograms (26.9%) achieved validity and 6 pictograms (11.5%) achieved partial validity. A greater proportion of pictograms for dose and route of administration, and dosage frequency achieved validity or partial validity versus those depicting precautions, indications or side effects., Conclusion: Majority (61.5%) of the assessed pictograms did not achieve validity or partial validity, highlighting the importance of contextual validation., Practice Implications: Low pictogram comprehension emphasizes the importance of facilitating pictogram understanding during medication counseling., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Little is known about pathophysiology of sarcopenia in diabetes. We aimed to study amino acid profile associated with skeletal muscle mass loss longitudinally in Type 2 Diabetes Mellitus (T2DM)., Methods: This is a prospective study of 1140 patients aged 56.6 ± 10.6 years from the SMART2D cohort. Skeletal muscle mass was measured using bio-impedance analysis at baseline and follow-up. Amino acids were measured by mass spectrometry., Results: Over a period of up to 7.9 years, 43.9% experienced skeletal muscle mass loss. Lower baseline valine, leucine and isoleucine levels were associated with decreased skeletal muscle mass index (SMI) with corresponding coefficient 0.251(95 %CI 0.009 to 0.493), 0.298(95 %CI 0.051 to 0.544)) and 0.366(95 %CI 0.131 to 0.600). Higher baseline valine, leucine, isoleucine, alanine and tryptophan levels were associated with reduced odds of muscle mass loss with corresponding odds ratio (OR)0.797 (95 %CI 0.690 to 0.921), 0.825 (95 %CI 0.713 to 0.955), 0.826 (95 %CI 0.718-0.950), 0.847 (95 %CI 0.739-0.969) and 0.835 (95 %CI 0.720-0.979)., Conclusion: The branched-chain amino acids valine, leucine and isoleucine were positively associated with change in SMI and reduced odds of muscle mass loss longitudinally. Further studies should be conducted to elucidate the pathophysiological mechanisms underlying the relationship between these amino acids and muscle mass loss in T2DM., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: In type 2 diabetes mellitus (T2DM), insulin therapy is often recommended to achieve the optimal control of disease, thereby preventing the onset and progression of diabetes-related complications. Despite knowing about the benefits, it has been reported that 71% of patients refuse insulin and the adherence rate ranges from 30 to 80%. Patient-provider relationship (PPR) may affect such insulin-related behaviours, but little is known about which aspect of PPR affects this. This study aimed to explore the key aspect of the patient-provider relationship that affects the initial insulin acceptance and continued adherence., Patients and Methods: We used the grounded theory approach in this qualitative research. The study was conducted at two primary care clinics between September 2019 and January 2021. Patients with T2DM on basal or premixed insulin were recruited using maximum variation sampling. Data were collected using semi-structured in-depth interviews and transcribed verbatim for analysis using constant comparison and synthesis., Results: Twenty-one participants with different levels of diabetes control and adherence were recruited. Four themes that emerged were 1) patient-provider interaction, 2) addressing the psychological fears, 3) gaining confidence in handling insulin equipment and 4) follow-up after insulin initiation. Among the subthemes, trust in doctors, provider's communication skills, patient-centred decision-making and continuity of care positively influenced insulin acceptance and adherence. Conversely, fear of being judged by the provider hindered open communication around non-adherence. Various aspects of interaction with nurses helped in alleviating patient's fear of injection and gaining confidence with the insulin equipment., Conclusion: Many aspects of PPR affect insulin acceptance and adherence. Among these, gaining patients' trust, effective patient-provider communication, patient-centred decision-making, and ensuring continuity of care improve both insulin acceptance and treatment adherence. Various interactions with nurses help in addressing fears surrounding injection and gaining acceptance towards insulin therapy. Patients' fear of being blamed or judged by the provider negatively affects open communication around non-adherence., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Mathew et al.)

Background: Insulin therapy forms a cornerstone of pharmacological management of diabetes mellitus (DM). However, there remains a lack of acceptance and adherence to insulin, thereby contributing to poor DM control. This study aimed to determine the impact of patients' beliefs about insulin on acceptance and adherence to insulin therapy., Method: This was a qualitative study using grounded theory approach. The study took place from September 2019 to January 2021 at a cluster of primary healthcare clinics in Singapore. Maximum variation sampling was used to recruit adult patients with type 2 DM on basal or premixed insulin for at least 6 months. Semistructured in-depth interviews were conducted using a topic guide and audio recorded. Data collection continued until saturation. Data analysis utilised a constant comparison procedure and a synthesis approach., Results: Twenty-one participants (mean age 61 years) were interviewed for this study. Data analyses showed that there were 6 main themes that emerged. Four themes influenced both insulin acceptance and adherence. These were concerns about insulin being a lifelong treatment, physical fear of insulin injection, erroneous beliefs about insulin, and perceived fear of DM complications. Two additional themes influenced adherence to insulin therapy. These were socioeconomic concerns, and concerns about side effects of insulin., Conclusions: Patients' beliefs about insulin impact on the acceptance and adherence to insulin therapy. Health care providers need to elicit and address these beliefs during counselling to improve acceptance and adherence to insulin therapy., (© 2022. The Author(s).)

Background: The association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use and cognitive function in type 2 diabetes remains unclear., Objective: Explore the association between SGLT2i and longitudinal changes in cognitive function in adults with type 2 diabetes (T2DM) and assessed the cognitive domains which were impacted by SGLT2i., Methods: We conducted a prospective cohort study of 476 patients aged 60.6±7.4 years with follow-up period up to 6.4 years. Data on SGLT2i use was derived from questionnaire and verified with clinical database. We used Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. The association between SGLT2i use and rate of RBANS score change was examined using multiple linear regression., Results: There were 138 patients (29.0%) on SGLT2i, including 84 (17.7%) for < 3 years and 54 (11.3%) for ≥3 years. SGLT2i use was positively associated with RBANS total score increase in language (coefficient 0.60; 95% CI 0.10-1.11; p = 0.019) in unadjusted analysis. This positive association persisted in fully adjusted model (coefficient 0.74; 95% CI 0.12 to 1.36; p = 0.019). SGLT2i use for ≥3 years was positively associated with RBANS score increase globally and in language domain in fully adjusted analysis with coefficients 0.54 (95% CI 0.13 to 0.95; p = 0.010) and 1.12 (95% CI 0.27 to 1.97; p = 0.010) respectively., Conclusion: Our findings revealed a previously unobserved association between ≥3 years SGLT2i use and improved cognitive scores globally and in language domain and executive function. Future studies should investigate the role of SGLT2i in ameliorating cognitive decline.

Introduction: Disease outbreaks such as the COVID-19 pandemic significantly heighten the psychological stress of healthcare workers (HCWs). The objective of this study was to understand the factors contributing to the perceived stress levels of HCWs in a public primary care setting during the COVID-19 pandemic, including their training, protection and support (TPS), job stress (JS), and perceived stigma and interpersonal avoidance., Methods: This cross-sectional study using an electronic self-administered questionnaire was conducted at the National Healthcare Group Polyclinics in March 2020. Data was collected anonymously. Analysis was performed using regression modelling., Results: The response rate was 69.7% (n = 1,040). The mean perceived stress level of HCWs in various departments ranged from 17.2 to 20.3. Respondents who reported higher perceived stress were those who made alternative living arrangements, were more affected by the current pandemic, reported higher JS and were Muslims. Respondents who reported lower perceived stress were those who had been through the severe acute respiratory syndrome epidemic in 2003 and H1N1 pandemic in 2009 as HCWs, and those who had higher confidence in the organisation's TPS., Conclusion: All HCWs, regardless of their scope of work, were similarly stressed by the current pandemic compared to the general population. Improving the confidence of HCWs in their training, protection and the support of personal protective equipment, and retaining experienced HCWs who can provide advice and emotional support to younger colleagues are important. Adequate psychological support for HCWs in the pandemic can be transformed into reserves of psychological resilience for future disease outbreaks., (Copyright: © Singapore Medical Association.)

Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM., Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients., Methods: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains., Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele., Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.

Context: Early-onset diabetes has been associated with unfavorable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce., Objective: We aimed to study the risk of, and risk factors for, incident HF in individuals with early-onset type 2 diabetes., Methods: We studied 606 individuals with type 2 diabetes diagnosed before 40 years of age (early-onset) and 1258 counterparts with diabetes diagnosed from 41 to 65 years of age (usual-onset) with no HF history, at a regional hospital, over a median follow-up period of 7.1 years. Incident HF by European Cardiology Society criteria was determined., Results: A total of 62 and 108 HF events were identified in the early- and usual-onset groups (1.55 and 1.29 per 100 patient-years), respectively. Compared with usual-onset counterparts, individuals with early-onset diabetes had a 1.20-fold unadjusted (95% CI, 0.88-1.63; P = 0.26) and 1.91-fold age-adjusted (95% CI, 1.37-2.66; P < 0.001) hazard ratio (HR) for incident HF. Adjustment for traditional cardiometabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69; 95% CI, 1.19-2.40; P = 0.003). However, additional adjustment for estimated glomerular filtration rate and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24; 95% CI, 0.87-1.77; P = 0.24). Notably, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures., Conclusion: Individuals with early-onset diabetes have at least the same absolute risk and a 2-fold age-adjusted relative risk for incident HF. Excess cardiorenal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein in the transforming growth factor-beta superfamily. We sought to study whether LRG1 might predict risk for all-cause and cause-specific mortality in individuals with type 2 diabetes., Methods: 2012 outpatients with type 2 diabetes were followed for a median of 7.2 years and 188 death events were identified. Association of LRG1 with risk for mortality was assessed by multivariable Cox regression models., Results: Participants with a higher concentration of LRG1 had an increased risk for all-cause mortality [HR (95% CI), 1.76 (1.03-3.01), 1.75 (1.03-2.98), and 4.37 (2.72-7.02) for quartiles 2, 3, and 4, respectively, compared to quartile 1]. The association remained significant after adjustment for known cardio-renal risk factors including estimated glomerular filtration rate and albuminuria [adjusted HR 2.76 (1.66-4.59), quartile 4 versus 1]. As a continuous variable, a 1-SD increment in LRG1 was associated with 1.34 (1.14-1.57)-fold adjusted risk for all-cause mortality. High plasma LRG1 was independently associated with mortality attributable to cardiovascular disease, infection, and renal diseases. Adding LRG1 into a clinical variable-based model improved discrimination (c statistics from 0.828 to 0.842, P = 0.006) and reclassification (net reclassification improvement 0.47, 95% CI 0.28-0.67) for prediction of 5-year all-cause mortality., Conclusion: Plasma LRG1 predicts risk for all-cause mortality and mortality attributable to cardiovascular disease, infection, and renal disease independent of known cardio-renal risk factors. It may be a potential novel biomarker to improve risk stratification in individuals with type 2 diabetes., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: To study the relationship between genetic risk of beta cell dysfunction, young onset age and glycaemic progression in individuals with type 2 diabetes (T2D)., Materials and Methods: 1385 T2D outpatients were included in cross-sectional sub-study and 730 insulin-naïve outpatients were followed for 3 years in prospective sub-study. Genetic risk score (GRS) was derived from 24 beta cell dysfunction-related single nucleotide polymorphisms, with lower and upper 25 percentiles defined as low and high genetic risk. Glycaemic progression was defined as requirement for sustained insulin therapy., Results: 388 participants in cross-sectional and 128 in prospective sub-study experienced glycaemic progression. Young onset age (T2D diagnosis below 40 year-old) was associated with high risk of glycaemic progression as compared to usual-onset counterparts (adjusted OR 1.64 [95% CI 1.14-2.36], and 2.92 [95% CI 1.76-4.87] in cross-sectional and prospective sub-study, respectively). As compared to those with intermediate risk, a low GRS was associated with lower risk for glycaemic progression (adjusted OR 0.72 [95% CI 0.49-1.06], and 0.51 [95% CI 0.29-0.90]) whereas a high GRS was not significantly associated with glycaemic progression. Notably, the association of young-onset T2D with high risk of glycaemic progression was independent of known clinical risk factors and beta cell dysfunction GRS (P interaction > 0.10)., Conclusion: Young onset age and low genetic risk of beta cell dysfunction are independently associated with risk of glycaemic progression. Our data do not support that genetic risk modulates the risk of glycaemic progression in individuals with young-onset T2D., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Prescription medication labels (PMLs) are an important source of written medication information for patients. However, real-world PMLs do not entirely conform with available labelling best practices and guidelines. Given this disconnect, older adults remain particularly at risk of misinterpreting their PMLs. Past studies have commonly assessed hypothetical PMLs, warranting studies that explore the lived experiences of older adults with real-world PMLs. Furthermore, the perspective of family caregivers of older adults is yet to be studied., Objectives: This qualitative study documented the challenges faced by older adults and their family caregivers in using real-world PMLs, their strategies to cope with these challenges, and their suggestions to improve existing PMLs., Methods: We conducted two focus group discussions ( n  = 17) and 30 in-depth interviews with older adults ( n  = 20; including those who can read in English and those with limited English proficiency) and caregivers ( n  = 10) in Singapore. The data were systematically assigned to codes that were continuously refined to accommodate emergent themes., Results: Challenges, coping strategies and suggested improvements were related to the comprehensibility, availability, readability and consistency of medication information on PMLs., Conclusions: Real-world PMLs continue to pose challenges for older adults and their caregivers, necessitating them to seek unique and personal coping strategies. The identified PML improvements, desired by older adults and their caregivers, urge healthcare systems to implement improved PMLs. Future research should explore system-level logistical, financial, and administrative barriers (or opportunities) that hinder (or facilitate) this implementation., Competing Interests: None, (© 2021 The Authors.)

Background: Singapore's healthcare system presents an ideal context to learn from diverse public and private operational models and funding systems., Aim: To explore processes underpinning decision-making for antibiotic prescribing, by considering doctors' experiences in different primary care settings., Methods: Thirty semi-structured interviews were conducted with 17 doctors working in publicly funded primary care clinics (polyclinics) and 13 general practitioners (GP) working in private practices (solo, small and large). Data were analysed using applied thematic analysis following realist principles, synthesised into a theoretical model, informing solutions to appropriate antibiotic prescribing., Results: Given Singapore's lack of national guidelines for antibiotic prescribing in primary care, practices are currently non-standardised. Themes contributing to optimal prescribing related first and foremost to personal valuing of reduction in antimicrobial resistance (AMR) which was enabled further by organisational culture creating and sustaining such values, and if patients were convinced of these too. Building trusting patient-doctor relationships, supported by reasonable patient loads among other factors were consistently observed to allow shared decision-making enabling optimal prescribing. Transparency and applying data to inform practice was a minority theme, nevertheless underpinning all levels of optimal care delivery. These themes are synthesised into the VALUE model proposed for guiding interventions to improve antibiotic prescribing practices. These should aim to reinforce intrapersonal Values consistent with prioritising AMR reduction, and Aligning organisational culture to these by leveraging standardised guidelines and interpersonal intervention tools. Such interventions should account for the wider systemic constraints experienced in publicly funded high patient turnover institutions, or private clinics with transactional models of care. Thus, ultimately a focus on Liaison between patient and doctor is crucial. For instance, building in adequate consultation time and props as discussion aids, or quick turnover communication tools in time-constrained settings. Message consistency will ultimately improve trust, helping to enable shared decision-making. Lastly, Use of monitoring data to track and Evaluate antibiotic prescribing using meaningful indicators, that account for the role of shared decision-making can also be leveraged for change., Conclusions: These VALUE dimensions are recommended as potentially transferable to diverse contexts, and the model as implementation tool to be tested empirically and updated accordingly., (© 2021. The Author(s).)

Background and Aims: Arterial stiffness is a risk factor for chronic kidney disease progression (CKD). Pulse pressure is a surrogate marker of arterial stiffness. It is unclear if pulse pressure predicts CKD progression in type 2 diabetes mellitus., Methods: This was prospective study involving 1494 patients with estimated glomerular filtration rate (eGFR) ≥ 15 ml/min/1.73 m 2 . Carotid-femoral pulse wave velocity was measured using applanation tonometry. Pulse pressure was calculated as difference between systolic and diastolic blood pressures. CKD progression was defined as worsening of eGFR categories (stage 1, ≥ 90 ml/min/1.73 m 2 ; stage 2, 60-89 ml/min/1.73 m 2 ; stage 3a, 45-59 ml/min/1.73 m 2 ; stage 3b, 30-44 ml/min/1.73 m 2 ; stage 4; 15-29 ml/min/1.73 m 2 ; and stage 5, < 15 ml/min/1.73 m 2 ) with ≥ 25% decrease in eGFR from baseline., Results: After follow-up of up to 6 years, CKD progression occurred in 33.5% of subjects. Subjects in 2nd, 3rd and 4th quartiles of peripheral pulse pressure experienced higher risk of CKD progression with unadjusted hazard ratios (HRs) 1.55 [95% confidence interval (CI) 1.13-2.11; p = 0.006], 2.58 (1.93-3.45; p < 0.001) and 3.41 (2.58-4.52; p < 0.001). In the fully adjusted model, the association for 2nd, 3rd and 4th quartiles remained with HRs 1.40 (1.02-1.93; p = 0.038), 1.87 (1.37-2.56; p < 0.001) and 1.75 (1.25-2.44; p = 0.001) respectively. Similarly, 2nd, 3rd and 4th quartiles of aortic pulse pressure were associated with higher hazards of CKD progression with HRs 1.73 (1.25-2.40; p = 0.001), 1.65 (1.18-2.29; p = 0.003) and 1.81 (1.26-2.60; p = 0.001). Increasing urinary albumin-to-creatinine ratio accounted for 44.0% of the association between peripheral pulse pressure and CKD progression., Conclusions: Individuals with high pulse pressure were more susceptible to deterioration of renal function. Pulse pressure could potentially be incorporated in clinical practice as an inexpensive and readily available biomarker of renal decline in type 2 diabetes mellitus. Graphic abstract., (© 2021. Italian Society of Nephrology.)

Background: A woman with a history of GDM has at least seven-fold increased lifetime risk of developing type 2 diabetes mellitus (T2DM), compared to women who have normoglycemic pregnancies. Postpartum lifestyle modification has been shown to reduce postpartum weight retention and prevent the progression to T2DM. The aim of this study was to explore the postpartum dietary and physical activity-related beliefs and behaviors among women in Singapore who had GDM in their most recent pregnancies., Methods: Semi-structured in-depth interviews were conducted with 14 women, who were up to four months postpartum and had GDM in their most recent pregnancies. Interview data were analyzed using thematic analysis., Results: Three themes were identified in the analysis: (1) risk perception and knowledge regarding future diabetes, (2) suboptimal diet and physical activity after delivery and (3) factors influencing the postpartum lifestyle., Conclusions: The study findings provided useful information on the postpartum lifestyle beliefs and behaviors among women with a history of GDM. Most participants had low risk perception of future diabetes and their diet and physical activity after delivery were suboptimal due to various influences. These insights can be used to design tailored materials and programs to support women who have had GDM reduce their risk of developing future T2DM., (© 2021. The Author(s).)

Context: Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain., Objectives: To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D., Design and Participants: We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater., Results: We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P < 0.05)., Conclusion: We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Genetic screening (GS), defined as the clinical testing of a population to identify asymptomatic individuals with the aim of providing those identified as high risk with prevention, early treatment, or reproductive options. Genetic screening (GS) improves patient outcomes and is accessible to the community. Family physicians (FPs) are ideally placed to offer GS. There is a need for FPs to adopt GS to address anticipated genetic specialist shortages., Objective: To explore FP attitudes, perceived roles, motivators and barriers, towards GS; and explore similarities and differences between private and public sector FPs., Methods: We developed a semi-structured interview guide using existing literature. We interviewed private and public sector FPs recruited by purposive, convenience and snowballing strategies, by telephone or video to theme saturation. All sessions were audio-recorded, transcribed and coded for themes by two independent researchers with an adjudicator., Results: Thirty FPs were interviewed (15 private, 15 public). Theme saturation was reached for each group. A total of 12 themes (6 common, 3 from private-practice participants, 3 public-employed participants) emerged. Six common major themes emerged: personal lack of training and experience, roles and relevance of GS to family medicine, reluctance and resistance to adding GS to practice, FP motivations for adoption, patient factors as barrier, and potential solutions. Three themes (all facilitators) were unique to the private group: strong rapport with patients, high practice autonomy, and high patient literacy. Three themes (all barriers) were unique to the public group: lack of control, patients' lower socioeconomic status, and rigid administrative infrastructure., Conclusion: FPs are motivated to incorporate GS but need support for implementation. Policy-makers should consider the practice setting when introducing new screening functions. Strategies to change FP behaviours should be sensitive to their sense of autonomy, and the external factors (either as facilitators or as barriers) shaping FP practices in a given clinical setting.

Aim: We studied the association between extracellular volume status and chronic kidney disease (CKD) progression; and the role of extracellular volume excess as a potential mediator in the relationship between matrix metalloproteinases (MMP)-2 and CKD progression in Type 2 diabetes mellitus (T2DM)., Methods: We conducted a prospective cohort study of 1079 T2DM patients. Bioelectrical impedance analysis (BIA) was performed to assess body fluid status., Results: After up to 8.6 years of follow-up, 471 (43.7%) patients experienced CKD progression. In the fully adjusted model, extracellular water (ECW)/ total body water (TBW)ratios 0.39-0.40 and > 0.40 were associated with 45% and 78% higher risk of CKD progression respectively. Patients with an increase in ECW/TBW ratio had 40% higher risk of CKD progression compared to those with no change or reduction of ECW/TBW ratio. Higher ECW/TBW ratio accounted for 17.4% of the relationship between MMP-2 and CKD progression in T2DM (p = 0.026)., Conclusions: Extracellular volume excess was independently associated with CKD progression in T2DM. Higher ECW/TBW ratio mediated the positive association between MMP-2 and CKD progression. Further studies are needed to elucidate the role of extracellular volume excess in deterioration of renal function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: We examined the longitudinal relationship between baseline skeletal muscle mass and its change over time with eGFR decline and albuminuria progression among Asians with type 2 diabetes(T2D)., Methods: This was a prospective cohort study of 1272 T2D patients. Skeletal muscle mass was estimated using tetra-polar multi-frequency bio-impedance analysis and Skeletal Muscle Mass Index(SMI) was defined as skeletal muscle mass/weight * 100., Results: After up to 8 years of follow-up, 33.3% of participants had CKD progression and 28.3% albuminuria progression. Every 1-SD above baseline SMI was associated with 18% lower risk of CKD progression[Hazards Ratio(HR)0.82; 95%CI 0.70-0.97; p = 0.018] and 17% lower risk of albuminuria progression [HR 0.83 (95%CI 0.71-0.97; p = 0.017)]. The largest decrease in SMI over time was associated with 67% higher risk of CKD progression, compared to those with the smallest change from baseline SMI tertile 2[HR 1.67 (95%CI 1.10-2.55); p = 0.016]. Pigment epithelium-derived factor(PEDF) and plasma leucine-rich α-2-glycoprotein (LRG1) accounted for 40.1% of the association between SMI and CKD progression., Conclusions: Low baseline skeletal muscle mass and its reduction over time is associated with increased risk of progression of CKD among Asians with T2D. PEDF and LRG1 mediated the inverse relationship between SMI and CKD progression., Competing Interests: Declaration of competing interests 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 B.V. All rights reserved.)

Aim: Little is known about whether overhydration (OH), measured using bioimpedance assay (BIA), is associated with CKD progression in patients with type 2 diabetes mellitus (T2DM). We hypothesised that OH was a predictor, and pigment epithelium-derived factor (PEDF) was a modifiable risk factor of CKD progression., Methods: We conducted a prospective cohort study of 1,065 patients with clinically euvolemic T2DM who attended the diabetes centre in a tertiary hospital or primary care clinic. CKD progression was defined as a combination of the worsening of the KDIGO defined CKD category by eGFR and a ≥25% decline in eGFR compared to baseline., Results: Patients with T2DM in the highest tertile of OH and relative OH (OH/ extracellular water > 7%) were positively associated with CKD progression (hazard ratio [HR] 1.45 [95% confidence interval (CI) 1.14-1.85; p = 0.003 and HR 1.29 [95%CI 1.05-1.59; p = 0.017]). There were positive associations between PEDF and CKD progression (β = 1.10; p = 0.001) and between OH and CKD progression (β = 0.21; p = 0.036). OH remained positively associated with CKD progression mediated by PEDF., Conclusions: OH is an independent risk factor for CKD progression in patients with T2DM. Our study supports the novel definition of PEDF as a positive mediator between OH and CKD progression., 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 B.V. All rights reserved.)

Background: Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach., Methods: The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m 2 , was assessed among 4768 (1628 cases and 3140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in T2D and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analyzed., Results: Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio   = 1.51, 95% confidence interval 1.12-2.12, P   =   0.007, P het   =   0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy ( β  = 0.010, P   =   0.751)., Conclusions: Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)