Asian females without diabetes are protected from obesity-related dysregulation of glucose metabolism compared with males.

OBJECTIVE: The impact of obesity on the risk for type 2 diabetes differs between males and females; however, the underlying reasons are unclear. This study aimed to investigate the effect of sex on obesity-driven changes in the mechanisms regulating glucose metabolism (insulin sensitivity and secretion) among Asian individuals without diabetes in Singapore. METHODS: The study assessed glucose tolerance using oral glucose tolerance test, insulin-mediated glucose uptake using hyperinsulinemic-euglycemic clamp, acute insulin response using an intravenous glucose challenge, and insulin secretion rates in the fasting state and in response to glucose ingestion using mathematical modeling in 727 males and 952 females who had normal body weight (n = 602, BMI < 23 kg/m2 ), overweight (n = 662, 23 ≤ BMI < 27.5), or obesity (n = 415, BMI ≥ 27.5). RESULTS: There were no sex differences among lean individuals. Obesity gradually worsened metabolic function, and the progressive adverse effects of obesity on insulin action and secretion were more pronounced in males than females, such that among participants with obesity, females had greater insulin sensitivity, lower insulin secretion, and lower fasting insulin concentration than males. The increase in waist to hip ratio with increasing BMI was more pronounced in males than females. CONCLUSIONS: The female sex exerts a protective effect on obesity-driven dysregulation of glucose metabolism in Asian individuals without diabetes.

Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes.

AIMS/HYPOTHESIS: Prediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of ß-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. METHODS: We recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, ß-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. RESULTS: Participants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and ß-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in ß-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and ß-cell function revealed a different pattern. CONCLUSIONS: Lower AIR to intravenous glucose and ß-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.

Stratification of Patients with Diabetes Using Continuous Glucose Monitoring Profiles and Machine Learning.

Background. Continuous glucose monitoring (CGM) offers an opportunity for patients with diabetes to modify their lifestyle to better manage their condition and for clinicians to provide personalized healthcare and lifestyle advice. However, analytic tools are needed to standardize and analyze the rich data that emerge from CGM devices. This would allow glucotypes of patients to be identified to aid clinical decision-making.Methods. In this paper, we develop an analysis pipeline for CGM data and apply it to 148 diabetic patients with a total of 8632 days of follow up. The pipeline projects CGM data to a lower-dimensional space of features representing centrality, spread, size, and duration of glycemic excursions and the circadian cycle. We then use principal components analysis and k-means to cluster patients' records into one of four glucotypes and analyze cluster membership using multinomial logistic regression.Results. Glucotypes differ in the degree of control, amount of time spent in range, and on the presence and timing of hyper- and hypoglycemia. Patients on the program had statistically significant improvements in their glucose levels.Conclusions. This pipeline provides a fast automatic function to label raw CGM data without manual input.

A Personalized Mobile Health Program for Type 2 Diabetes During the COVID-19 Pandemic: Single-Group Pre-Post Study.

BACKGROUND: With increasing type 2 diabetes prevalence, there is a need for effective programs that support diabetes management and improve type 2 diabetes outcomes. Mobile health (mHealth) interventions have shown promising results. With advances in wearable sensors and improved integration, mHealth programs could become more accessible and personalized. OBJECTIVE: The study aimed to evaluate the feasibility, acceptability, and effectiveness of a personalized mHealth-anchored intervention program in improving glycemic control and enhancing care experience in diabetes management. The program was coincidentally implemented during the national-level lockdown for COVID-19 in Singapore, allowing for a timely study of the use of mHealth for chronic disease management. METHODS: Patients with type 2 diabetes or prediabetes were enrolled from the Singapore Armed Forces and offered a 3-month intervention program in addition to the usual care they received. The program was standardized to include (1) in-person initial consultation with a clinical dietitian; (2) in-person review with a diabetes specialist doctor; (3) 1 continuous glucose monitoring device; (4) access to the mobile app for dietary intake and physical activity tracking, and communication via messaging with the dietitian and doctor; and (5) context-sensitive digital health coaching over the mobile app. Medical support was rendered to the patients on an as-needed basis when they required advice on adjustment of medications. Measurements of weight, height, and glycated hemoglobin A1c (HbA1c) were conducted at 2 in-person visits at the start and end of the program. At the end of the program, patients were asked to complete a short acceptability feedback survey to understand the motivation for joining the program, their satisfaction, and suggestions for improvement. RESULTS: Over a 4-week recruitment period, 130 individuals were screened, the enrollment target of 30 patients was met, and 21 patients completed the program and were included in the final analyses; 9 patients were lost to follow-up (full data were not available for the final analyses). There were no differences in the baseline characteristics between patients who were included and excluded from the final analyses (age category: P=.23; gender: P=.21; ethnicity: P>.99; diabetes status category: P=.52, medication adjustment category: P=.65; HbA1c category: P=.69; BMI: P>.99). The 21 patients who completed the study rated a mean of 9.0 out of 10 on the Likert scale for both satisfaction questions. For the Yes-No question on benefit of the program, all of the patients selected "Yes." Mean HbA1c decreased from 7.6% to 7.0% (P=.004). There were no severe hypoglycemia events (glucose level <3.0 mmol/L) reported. Mean weight decreased from 76.8 kg to 73.9 kg (P<.001), a mean decrease of 3.5% from baseline weight. Mean BMI decreased from 27.8 kg/m2 to 26.7 kg/m2 (P<.001). CONCLUSIONS: The personalized mHealth program was feasible, acceptable, and produced significant reductions in HbA1c (P=.004) and body weight (P<.001) in individuals with type 2 diabetes. Such mHealth programs could overcome challenges posed to chronic disease management by COVID-19, including disruptions to in-person health care access.

The impact of COVID-19 on private and public primary care physicians: A cross-sectional study.

PURPOSE: Primary care physicians (PCP) are at a high risk of contracting COVID-19 as they manage patients with fever or respiratory symptoms, but it is intuitive that private and public practice PCPs may face different challenges during this pandemic. This study compared work- and non-work-related concerns, COVID-19's impact on personal and professional lives, and perceived pandemic preparedness between private and public PCPs in Singapore. METHODS: 216 PCPs who were a registered member of either the National University Polyclinics, National University Health System Primary Care Network or College of Family Physicians Singapore, participated in this online cross-sectional study. The data collection period lasted from 6th March 2020 to 29th March 2020. RESULTS: A final sample of 172 questionnaires were analysed. Private PCPs tended to be older and more experienced. Perceived COVID-19 exposure and overall preparedness was high in both groups. More private PCPs perceived their exposure risk as unacceptable, aOR = 3.96 (1.07, 14.62); that they should not be caring for COVID-19 patients, aOR = 3.55 (1.23, 10.24); and perceived more stigma against their loved ones, aOR = 4.27 (1.74, 10.44). Private PCPs felt less well-trained, aOR = 0.05 (0.01, 0.23); and supported, aOR = 0.14 (0.03, 0.63). CONCLUSIONS: Private PCPs are more likely to be self-employed or work in smaller practices where COVID-19 infection could mean loss of livelihood. As a healthcare system without primary care is crippled in its ability to manage outbreaks, authorities should respond appropriately to the needs of their general practitioners and family physicians.

CD10 marks non-canonical PPARγ-independent adipocyte maturation and browning potential of adipose-derived stem cells.

BACKGROUND: Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. However, limitations in our understanding and the lack of reliable markers that can predict their maturation efficacies have hindered the development of stem cells as an effective therapeutic strategy. Our previous study identified CD10, a pro-adipogenic, depot-specific prospective cell surface marker of human adipose-derived stem cells (ASCs). Here, we aim to determine if CD10 can be used as a prospective marker to predict mature adipocyte quality and play a direct role in adipocyte maturation. METHODS: We first generated 14 primary human subject-derived ASCs and stable immortalized CD10 knockdown and overexpression lines for 4 subjects by the lentiviral transduction system. To evaluate the role of CD10 in adipogenesis, the adipogenic potential of the human subject samples were scored against their respective CD10 transcript levels. Assessment of UCP1 expression levels was performed to correlate CD10 levels to the browning potential of mature ASCs. Quantitative polymerase chain reaction (qPCR) and Western blot analysis were performed to determine CD10-dependent regulation of various targets. Seahorse analysis of oxidative metabolism and lipolysis assay were studied. Lastly, as a proof-of-concept study, we used CD10 as a prospective marker for screening nuclear receptor ligands library. RESULTS: We identified intrinsic CD10 levels as a positive determinant of adipocyte maturation as well as browning potential of ASCs. Interestingly, CD10 regulates ASC's adipogenic maturation non-canonically by modulating endogenous lipolysis without affecting the classical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent adipogenic pathways. Furthermore, our CD10-mediated screening analysis identified dexamethasone and retinoic acid as stimulator and inhibitor of adipogenesis, respectively, indicating CD10 as a useful biomarker for pro-adipogenic drug screening. CONCLUSION: Overall, we establish CD10 as a functionally relevant ASC biomarker, which may be a prerequisite to identify high-quality cell populations for improving metabolic diseases.

Prepared and highly committed despite the risk of COVID-19 infection: a cross-sectional survey of primary care physicians' concerns and coping strategies in Singapore.

BACKGROUND: Primary care physicians (PCPs) are first points-of-contact between suspected cases and the healthcare system in the current COVID-19 pandemic. This study examines PCPs' concerns, impact on personal lives and work, and level of pandemic preparedness in the context of COVID-19 in Singapore. We also examine factors and coping strategies that PCPs have used to manage stress during the outbreak. METHODS: Two hundred and sixteen PCPs actively practicing in either a public or private clinic were cluster sampled via email invitation from three primary care organizations in Singapore from 6th to 29th March 2020. Participants completed a cross-sectional online questionnaire consisting of items on work- and non-work-related concerns, impact on personal and work life, perceived pandemic preparedness, stress-reduction factors, and personal coping strategies related to COVID-19. RESULTS: A total of 158 questionnaires were usable for analyses. PCPs perceived themselves to be at high risk of COVID-19 infection (89.9%), and a source of risk (74.7%) and concern (71.5%) to loved ones. PCPs reported acceptance of these risks (91.1%) and the need to care for COVID-19 patients (85.4%). Overall perceived pandemic preparedness was extremely high (75.9 to 89.9%). PCPs prioritized availability of personal protective equipment, strict infection prevention guidelines, accessible information about COVID-19, and well-being of their colleagues and family as the most effective stress management factors. CONCLUSIONS: PCPs continue to serve willingly on the frontlines of this pandemic despite the high perception of risk to themselves and loved ones. Healthcare organizations should continue to support PCPs by managing both their psychosocial (e.g. stress management) and professional (e.g. pandemic preparedness) needs.

Exploring the dimensions of patient experience for community-based care programmes in a multi-ethnic Asian context.

INTRODUCTION: The aim of this study is to explore patients' experiences with community-based care programmes (CCPs) and develop dimensions of patient experience salient to community-based care in Singapore. Most countries like Singapore are transforming its healthcare system from a hospital-centric model to a person-centered community-based care model to better manage the increasing chronic disease burden resulting from an ageing population. It is thus critical to understand the impact of hospital to community transitions from the patients' perspective. The exploration of patient experience will guide the development of an instrument for the evaluation of CCPs for quality improvement purposes. METHODS: A qualitative exploratory study was conducted where face-to-face in-depth interviews were conducted using a purposive sampling method with patients enrolled in CCPs. In total, 64 participants aged between 41 to 94 years were recruited. A deductive framework was developed using the Picker Patient Experience instrument to guide our analysis. Inductive coding was also conducted which resulted in emergence of new themes. RESULTS: Our findings highlighted eight key themes of patient experience: i) ensuring care continuity, ii) involvement of family, iii) access to emotional support, vi) ensuring physical comfort, v) coordination of services between providers, vi) providing patient education, vii) importance of respect for patients, and viii) healthcare financing. CONCLUSION: Our results demonstrated that patient experience is multi-faceted, and dimensions of patient experience vary according to healthcare settings. As most patient experience frameworks were developed based on a single care setting in western populations, our findings can inform the development of a culturally relevant instrument to measure patient experience of community-based care for a multi-ethnic Asian context.

Shifting care from hospital to community, a strategy to integrate care in Singapore: process evaluation of implementation fidelity.

BACKGROUND: Accessibility to efficient and person-centered healthcare delivery drives healthcare transformation in many countries. In Singapore, specialist outpatient clinics (SOCs) are commonly congested due to increasing demands for chronic care. To improve this situation, the National University Health System (NUHS) Regional Health System (RHS) started an integrated care initiative,the Right-Site Care (RSC) program in 2014. Through collaborations between SOCs at the National University Hospital and primary and community care (PCC) clinics in the western region of the county, the program was designed to facilitate timely discharge and appropriate transition of patients, who no longer required specialist care, to the community. The aim of this study was to evaluate the implementation fidelity of the NUHS RHS RSC program using the modified Conceptual Framework for Implementation Fidelity (CFIF), at three distinct levels; providers, organizational, and system levels to explain outcomes of the program and to inform further development of (similar) programs. METHODS: A convergent parallel mixed methods study using the realist evaluation approach was used. Data were collected between 2016 and 2018 through non-participatory observations, reviews of medical records and program database, together with semi-structured interviews with healthcare providers. Triangulation of data streams was applied guided by the modified CFIF. RESULTS: Our findings showed four out of six program components were implemented with low level of fidelity, and 9112 suitable patients were referred to the program while 3032 (33.3%) declined to be enrolled. Moderating factors found to influence fidelity included: (i) complexity of program, (ii) evolving providers' responsiveness, (iii) facilitation through synergistic partnership, training of PCC providers by specialists and supportive structures: care coordinators, guiding protocols, shared electronic medical record and shared pharmacy, (iv) lack of organization reinforcement, and (v) mismatch between program goals, healthcare financing and providers' reimbursement. CONCLUSION: Functional integration alone is insufficient for a successful right-site care program implementation. Improvement in relationships between providers, organizations, and patients are also warranted for further development of the program.

Autoimmune responses and inflammation in type 2 diabetes.

Obesity-induced insulin resistance is one of the largest noncommunicable disease epidemics that we are facing at the moment. Changes in lifestyle and greater availability of low nutritional value, high caloric food has led to the highest rates of obesity in history. Obesity impacts the immune system and obesity-associated inflammation contributes to metabolic diseases, such as type 2 diabetes. Both the adaptive and the innate immune system play a role in the regulation of glycemic control, and there is a need to understand how metabolic imbalances drive disease pathogenesis. This review discusses the cell types, mediators, and pathways that contribute to immunologic-metabolic crosstalk and explores how the immune system might be targeted as a strategy to treat metabolic disease.

Conducting a Cost-Benefit Analysis of Transitional Care Programmes: The Key Challenges and Recommendations.

Transitional care encompasses a range of services designed to promote care integration as patients transfer between different locations or different levels of care. Transitional care programmes have been proven to produce positive outcomes in reducing hospital readmissions and improving patients' health outcomes. However, little is known about the benefits of the programmes on healthcare cost and the published results have been inconsistent. With increasing healthcare expenditures and limited public healthcare resources, cost-benefit analyses become paramount in informing healthcare resource allocation decisions. This perspective paper describes the approaches used in estimating the total costs of a bundle of transitional care services from an academic medical centre, identifies the key methodological challenges encountered in the process of cost-benefit analysis, and recommends potential solutions to tackle these challenges. By providing a comprehensive perspective on the methodological challenges, this paper encourages program evaluators to take these possible challenges into consideration for future cost-benefit analyses.

Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation.

INTRODUCTION AND OBJECTIVE: Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs. RESEARCH DESIGN AND METHODS: In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation. RESULTS: Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation. CONCLUSIONS: Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.

Characterising and predicting persistent high-cost utilisers in healthcare: a retrospective cohort study in Singapore.

OBJECTIVE: We aim to characterise persistent high utilisers (PHUs) of healthcare services, and correspondingly, transient high utilisers (THUs) and non-high utilisers (non-HUs) for comparison, to facilitate stratifying HUs for targeted intervention. Subsequently we apply machine learning algorithms to predict which HUs will persist as PHUs, to inform future trials testing the effectiveness of interventions in reducing healthcare utilisation in PHUs. DESIGN AND SETTING: This is a retrospective cohort study using administrative data from an Academic Medical Centre (AMC) in Singapore. PARTICIPANTS: Patients who had at least one inpatient admission to the AMC between 2005 and 2013 were included in this study. HUs incurred Singapore Dollar 8150 or more within a year. PHUs were defined as HUs for three consecutive years, while THUs were HUs for 1 or 2 years. Non-HUs did not incur high healthcare costs at any point during the study period. OUTCOME MEASURES: PHU status at the end of the third year was the outcome of interest. Socio-demographic profiles, clinical complexity and utilisation metrics of each group were reported. Area under curve (AUC) was used to identify the best model to predict persistence. RESULTS: PHUs were older and had higher comorbidity and mortality. Over the three observed years, PHUs' expenditure generally increased, while THUs and non-HUs' spending and inpatient utilisation decreased. The predictive model exhibited good performance during both internal (AUC: 83.2%, 95% CI: 82.2% to 84.2%) and external validation (AUC: 79.8%, 95% CI: 78.8% to 80.8%). CONCLUSIONS: The HU population could be stratified into PHUs and THUs, with distinctly different utilisation trajectories. We developed a model that could predict at the end of 1 year, whether a patient in our population will continue to be a HU in the next 2 years. This knowledge would allow healthcare providers to target PHUs in our health system with interventions in a cost-effective manner.

Two-Hour Postprandial Lipoprotein Particle Concentration Differs Between Lean and Obese Individuals.

The concentrations of lipoprotein particles [high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), and chylomicrons] are associated with the risk of cardiovascular diseases. Most studies have examined these associations in the fasting state. Previous studies have shown lipoprotein particle concentration change following meal, and these changes are different in individuals with obesity. In this study, we aimed to assess whether various meal compositions lead to adverse short-term (2-h) postprandial lipoproteinemia in obese insulin resistant (obese-IR) subjects as compared to lean insulin sensitive (lean-IS) subjects. In a randomized crossover trial, nine lean-IS and nine obese-IR Chinese men aged 22-35 years were challenged with isoenergetic and isovolumic meals rich in protein (HP), fat (HF), or carbohydrate (HC). Plasma samples were collected after a 10-h fast, as well as 1-h and 2-h post-meal and analyzed using nuclear magnetic resonance. Plasma concentration of large VLDLs and chylomicron particles was higher and increased more after all meals in obese-IR compared to lean-IS subjects. The HP meal decreased small LDL particle concentration in obese-IR subjects, and increased small HDL particle concentration in all subjects. The HF meal led to a decrease in small HDL concentration in all subjects. In conclusion, obese-IR subjects revealed a detrimental response to meal challenges even as early as 2-h after meal intake.

Characterization of high healthcare utilizer groups using administrative data from an electronic medical record database.

BACKGROUND: High utilizers (HUs) are a small group of patients who impose a disproportionately high burden on the healthcare system due to their elevated resource use. Identification of persistent HUs is pertinent as interventions have not been effective due to regression to the mean in majority of patients. This study will use cost and utilization metrics to segment a hospital-based patient population into HU groups. METHODS: The index visit for each adult patient to an Academic Medical Centre in Singapore during 2006 to 2012 was identified. Cost, length of stay (LOS) and number of specialist outpatient clinic (SOC) visits within 1 year following the index visit were extracted and aggregated. Patients were HUs if they exceeded the 90th percentile of any metric, and Non-HU otherwise. Seven different HU groups and a Non-HU group were constructed. The groups were described in terms of cost and utilization patterns, socio-demographic information, multi-morbidity scores and medical history. Logistic regression compared the groups' persistence as a HU in any group into the subsequent year, adjusting for socio-demographic information and diagnosis history. RESULTS: A total of 388,162 patients above the age of 21 were included in the study. Cost-LOS-SOC HUs had the highest multi-morbidity and persistence into the second year. Common conditions among Cost-LOS and Cost-LOS-SOC HUs were cardiovascular disease, acute cerebrovascular disease and pneumonia, while most LOS and LOS-SOC HUs were diagnosed with at least one mental health condition. Regression analyses revealed that HUs across all groups were more likely to persist compared to Non-HUs, with stronger relationships seen in groups with high SOC utilization. Similar trends remained after further adjustment. CONCLUSION: HUs of healthcare services are a diverse group and can be further segmented into different subgroups based on cost and utilization patterns. Segmentation by these metrics revealed differences in socio-demographic characteristics, disease profile and persistence. Most HUs did not persist in their high utilization, and high SOC users should be prioritized for further longitudinal analyses. Segmentation will enable policy makers to better identify the diverse needs of patients, detect gaps in current care and focus their efforts in delivering care relevant and tailored to each segment.

Retrospective evaluation of healthcare utilisation and mortality of two post-discharge care programmes in Singapore.

OBJECTIVE: To evaluate the impact on healthcare utilisation frequencies and charges, and mortality of a programme for frequent hospital utilisers and a programme for patients requiring high acuity post-discharge care as part of an integrated healthcare model. DESIGN: A retrospective quasi-experimental study without randomisation where patients who received post-discharge care interventions were matched 1:1 with unenrolled patients as controls. SETTING: The National University Health System (NUHS) Regional Health System (RHS), which was one of six RHS in Singapore, implemented the NUHS RHS Integrated Interventions and Care Extension (NICE) programme for frequent hospital utilisers and the NUHS Transitional Care Programme (NUHS TCP) for high acuity post-discharge care. The programmes were supported by the Ministry of Health in Singapore, which is a city-state nation located in Southeast Asia with a 5.6 million population. PARTICIPANTS: Linked healthcare administrative data, for the time period of January 2013 to December 2016, were extracted for patients enrolled in NICE (n=554) or NUHS TCP (n=270) from June 2014 to December 2015, and control patients. INTERVENTIONS: For both programmes, teams conducted follow-up home visits and phone calls to monitor and manage patients' post-discharge. PRIMARY OUTCOME MEASURES: One-year pre- and post-enrolment healthcare utilisation frequencies and charges of all-cause inpatient admissions, emergency admissions, emergency department attendances, specialist outpatient clinic (SOC) attendances, total inpatient length of stay and mortality rates were compared. RESULTS: Patients in NICE had lower mortality rate, but higher all-cause inpatient admission, emergency admission and emergency department attendance charges. Patients in NUHS TCP did not have lower mortality rate, but had higher emergency admission and SOC attendance charges. CONCLUSIONS: Both NICE and NUHS TCP had no improvements in 1 year healthcare utilisation across various setting and metrics. Singular interventions might not be as impactful in effecting utilisation without an overhauling transformation and restructuring of the hospital and healthcare system.

Oxidative stress mediates depot-specific functional differences of human adipose-derived stem cells.

BACKGROUND: Visceral (VS) fat depot is known to have defective adipogenic functions compared to subcutaneous (SC) fat, but its mechanism of origin is unclear. OBJECTIVE: We tested our hypothesis that the degree of oxidative stress in adipose-derived stem cells (ASCs) from these depots may account for this difference. METHODS: ASCs were isolated from VS (omental region) and SC (abdominal region) fat depots of human subjects undergoing bariatric surgery. ASCs from VS and SC fat were investigated for their cellular characteristics in reactive oxygen species (ROS), metabolism, gene expression, proliferation, senescence, migration, and adipocyte differentiation. ASCs were also treated with antioxidant ascorbic acid (vitamin C). RESULTS: We found that human VS-derived ASCs exhibit excessive oxidative stress characterized by high reactive oxygen species (ROS), compared to SC-derived ASCs. Gene expression analyses indicate that the VS-ASCs exhibit higher levels of genes involved in pro-oxidant and pro-inflammatory pathways and lower levels of genes in antioxidant and anti-inflammatory pathways. VS-ASCs have impaired cellular functions compared to SC-ASCs, such as slower proliferation, early senescence, less migratory activity, and poor adipogenic capability in vitro. Treatment with ascorbic acid decreased ROS levels drastically in VS-ASCs. Ascorbic acid treatment substantially improved proliferation, senescence, migration, and adipogenic capacities of compromised ASCs caused by high ROS. CONCLUSIONS: This finding suggests the fat depot-specific differences of cellular defects originating from stem cell population. Considering clinical potentials of human ASCs for cell therapies, this also offers a possible strategy for improving their therapeutic qualities through antioxidants.

Genes Involved in Oxidative Stress Pathways Are Differentially Expressed in Circulating Mononuclear Cells Derived From Obese Insulin-Resistant and Lean Insulin-Sensitive Individuals Following a Single Mixed-Meal Challenge.

Background: Oxidative stress induced by nutritional overload has been linked to the pathogenesis of insulin resistance, which is associated with metabolic syndrome, obesity, type 2 diabetes and diabetic vascular complications. Postprandial changes in expression of oxidative stress pathway genes in obese vs. lean individuals, following intake of different types of meals varying in macronutrient composition have not been characterized to date. Here we aimed to test whether/how oxidative stress responses in obese vs. lean individuals are modulated by meal composition. Methods: High-carbohydrate (HC), high-fat (HF), or high-protein (HP) liquid mixed meals were administered to study subjects (lean insulin-sensitive, n = 9 and obese insulin-resistant, n = 9). Plasma levels of glucose and insulin, lipid profile, urinary F2-isoprostanes (F2-IsoP), and expression levels of genes of oxidative stress pathways were assessed in mononuclear cells (MNC) derived from fresh peripheral blood, at baseline and up to 6-h postprandial states. Differences in these parameters were compared between insulin-sensitive/resistant groups undergoing aforementioned meal challenges. Results: Obese individuals exhibited increased pro-oxidant (i.e., CYBB and CYBA) and anti-oxidant (i.e., TXN RD1) gene expression in the postprandial state, compared with lean subjects, regardless of meal type (P interaction for group × time < 0.05). By contrast, lean subjects had higher expression of NCF-4 gene (pro-oxidant) after HC meal and SOD1 gene (anti-oxidant) after HC and HF meals (P interaction for group × meal < 0.05). There was an increase in postprandial level of urinary F2-IsoP in the obese (P < 0.05) but not lean group. Conclusions: These findings may represent an adaptive oxidative response to mitigate increased stress induced by acute nutritional excess. Further, the results suggest an increased predisposition of obese subjects to oxidative stress. Chronic nutritional excess resulting in increases in body weight and adiposity might lead to decompensation leading to worsening insulin resistance and its sequel. Insights from this study could impact on nutritional recommendations for obese subjects at high-risk of cardiovascular diseases.

Plasma Protein and MicroRNA Biomarkers of Insulin Resistance: A Network-Based Integrative -Omics Analysis.

Although insulin resistance (IR) is a key pathophysiologic condition underlying various metabolic disorders, impaired cellular glucose uptake is one of many manifestations of metabolic derangements in the human body. To study the systems-wide molecular changes associated with obesity-dependent IR, we integrated information on plasma proteins and microRNAs in eight obese insulin-resistant (OIR, HOMA-IR > 2.5) and nine lean insulin-sensitive (LIS, HOMA-IR < 1.0) normoglycemic males. Of 374 circulating miRNAs we profiled, 65 species increased and 73 species decreased in the OIR compared to the LIS subjects, suggesting that the overall balance of the miRNA secretome is shifted in the OIR subjects. We also observed that 40 plasma proteins increased and 4 plasma proteins decreased in the OIR subjects compared to the LIS subjects, and most proteins are involved in metabolic and endocytic functions. We used an integrative -omics analysis framework called iOmicsPASS to link differentially regulated miRNAs with their target genes on the TargetScan map and the human protein interactome. Combined with tissue of origin information, the integrative analysis allowed us to nominate obesity-dependent and obesity-independent protein markers, along with potential sites of post-transcriptional regulation by some of the miRNAs. We also observed the changes in each -omics platform that are not linked by the TargetScan map, suggesting that proteins and microRNAs provide orthogonal information for the progression of OIR. In summary, our integrative analysis provides a network of elevated plasma markers of OIR and a global shift of microRNA secretome composition in the blood plasma.