A fully convolutional neural network for comprehensive compartmentalization of abdominal adipose tissue compartments in MRI.

BACKGROUND: Existing literature has highlighted structural, physiological, and pathological disparities among abdominal adipose tissue (AAT) sub-depots. Accurate separation and quantification of these sub-depots are crucial for advancing our understanding of obesity and its comorbidities. However, the absence of clear boundaries between the sub-depots in medical imaging data has challenged their separation, particularly for internal adipose tissue (IAT) sub-depots. To date, the quantification of AAT sub-depots remains challenging, marked by a time-consuming, costly, and complex process. PURPOSE: To implement and evaluate a convolutional neural network to enable granular assessment of AAT by compartmentalization of subcutaneous adipose tissue (SAT) into superficial subcutaneous (SSAT) and deep subcutaneous (DSAT) adipose tissue, and IAT into intraperitoneal (IPAT), retroperitoneal (RPAT), and paraspinal (PSAT) adipose tissue. MATERIAL AND METHODS: MRI datasets were retrospectively collected from Singapore Preconception Study for Long-Term Maternal and Child Outcomes (S-PRESTO: 389 women aged 31.4 ± 3.9 years) and Singapore Adult Metabolism Study (SAMS: 50 men aged 28.7 ± 5.7 years). For all datasets, ground truth segmentation masks were created through manual segmentation. A Res-Net based 3D-UNet was trained and evaluated via 5-fold cross-validation on S-PRESTO data (N = 300). The model's final performance was assessed on a hold-out (N = 89) and an external test set (N = 50, SAMS). RESULTS: The proposed method enabled reliable segmentation of individual AAT sub-depots in 3D MRI volumes with high mean Dice similarity scores of 98.3%, 97.2%, 96.5%, 96.3%, and 95.9% for SSAT, DSAT, IPAT, RPAT, and PSAT respectively. CONCLUSION: Convolutional neural networks can accurately sub-divide abdominal SAT into SSAT and DSAT, and abdominal IAT into IPAT, RPAT, and PSAT with high accuracy. The presented method has the potential to significantly contribute to advancements in the field of obesity imaging and precision medicine.

Management of Recurrent HPV-Positive Oropharyngeal Squamous Cell Carcinoma: a Contemporary Review.

PURPOSE OF REVIEW: To review the impact of contemporary treatment strategies on salvage outcomes in patients with recurrent human papilloma virus-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). RECENT FINDINGS: Secondary to HPV, changes in disease biology have impacted primary treatments and subsequent approaches to patients with recurrence. With treatment strategies more inclusive of upfront surgery, the characteristics of patients with recurrence HPV + OPSCC have been further redefined. Less invasive endoscopic surgical approaches such as transoral robotic surgery (TORS), and the continued refinement of conformal radiotherapy techniques, have improved treatment options for patients with recurrent HPV + OPSCC. Systemic treatment options have continued to expand including potentially effective immune-based therapies. Effective surveillance with systemic and oral biomarkers offers hope of earlier detection of recurrence. Management of patients with recurrent OPSCC remains difficult. Modest improvements in salvage treatment have been observed within the HPV + OPSCC cohort largely reflecting disease biology and improved treatment techniques.

Branched Chain Amino Acid Supplementation to a Hypocaloric Diet Does Not Affect Resting Metabolic Rate but Increases Postprandial Fat Oxidation Response in Overweight and Obese Adults after Weight Loss Intervention.

BACKGROUND: Branched chain amino acids (BCAA) supplementation is reported to aid in lean mass preservation, which may in turn minimize the reduction in resting metabolic rate (RMR) during weight loss. Our study aimed to examine the effect of BCAA supplementation to a hypocaloric diet on RMR and substrate utilization during a weight loss intervention. METHODS: A total of 111 Chinese subjects comprising 55 males and 56 females aged 21 to 45 years old with BMI between 25 and 36 kg/m2 were randomized into three hypocaloric diet groups: (1) standard-protein (14%) with placebo (CT), (2) standard-protein with BCAA, and (3) high-protein (27%) with placebo. Indirect calorimetry was used to measure RMR, carbohydrate, and fat oxidation before and after 16 weeks of dietary intervention. RESULTS: RMR was reduced from 1600 ± 270 kcal/day to 1500 ± 264 kcal/day (p < 0.0005) after weight loss, but no significant differences in the change of RMR, respiratory quotient, and percentage of fat and carbohydrate oxidation were observed among the three diet groups. Subjects with BCAA supplementation had an increased postprandial fat (p = 0.021) and decreased postprandial carbohydrate (p = 0.044) oxidation responses compared to the CT group after dietary intervention. CONCLUSIONS: BCAA-supplemented standard-protein diet did not significantly attenuate reduction of RMR compared to standard-protein and high-protein diets. However, the postprandial fat oxidation response increased after BCAA-supplemented weight loss intervention.

Branched-Chain Amino Acid Supplementation Does Not Preserve Lean Mass or Affect Metabolic Profile in Adults with Overweight or Obesity in a Randomized Controlled Weight Loss Intervention.

BACKGROUND: Branched-chain amino acid (BCAA) supplementation has been shown to increase muscle mass or prevent muscle loss during weight loss. OBJECTIVE: We aimed to investigate the effects of a BCAA-supplemented hypocaloric diet on lean mass preservation and insulin sensitivity. METHODS: A total of 132 Chinese adults (63 men and 69 women aged 21-45 y, BMI 25-36 kg/m2) were block randomly assigned by gender and BMI into 3 hypocaloric diet (deficit of 500 kcal/d) groups: standard-protein (14%) with placebo (control, CT) or BCAA supplements at 0.1 g · kg-1 body weight · d-1 (BCAA) or high-protein (27%) with placebo (HP). The subjects underwent 16 wk of dietary intervention with provision of meals and supplements, followed by 8 wk of weight maintenance with provision of supplements only. One-way ANOVA analysis was conducted to analyze the primary (lean mass and insulin sensitivity) and secondary outcomes (anthropometric and metabolic parameters) among the 3 groups. Paired t-test was used to analyze the change in each group. RESULTS: The 3 groups demonstrated similar significant reductions in body weight (7.97%), fat mass (13.8%), and waist circumference (7.27%) after 16 wk of energy deficit. Lean mass loss in BCAA (4.39%) tended to be lower than in CT (5.39%) and higher compared with HP (3.67%) (P = 0.06). Calf muscle volume increased 3.4% in BCAA and intramyocellular lipids (IMCLs) decreased in BCAA (17%) and HP (18%) (P < 0.05) over 16 wk. During the 8 wk weight maintenance period, lean mass gain in BCAA (1.03%) tended to be lower compared with CT (1.58%) and higher than in HP (-0.002%) (P = 0.04). Lean mass gain differed significantly between CT and HP (P = 0.03). Insulin sensitivity and metabolic profiles did not differ among the groups throughout the study period. CONCLUSIONS: BCAA supplementation does not preserve lean mass or affect insulin sensitivity in overweight and obese adults during weight loss. A higher protein diet may be more advantageous for lean mass preservation.

Long-term outcomes of ischaemic stroke patients with diabetes in a multi-ethnic cohort in Singapore.

INTRODUCTION: Diabetes increases the risk of ischaemic stroke especially among Asians. This study aims to investigate contemporaneous long-term cardiovascular outcomes of ischaemic stroke patients with diabetes in a multi-ethnic Asian cohort. METHODS: Consecutive patients with ischaemic stroke were recruited from the National University Hospital, Singapore. Data on age, gender, ethnicity, risk factors (including diabetes status and body mass index [BMI]), stroke severity and mechanisms were collected. These patients were followed up until the day of the first cardiovascular event or July 2016, whichever was earlier. The primary endpoint was the time from enrolment to the first occurrence of a composite of cerebrovascular and coronary artery events. RESULTS: Between July 2011 and December 2013, 720 patients (mean age 60.6 years, 71% men, 43% with diabetes, median National Institute Health Stroke Severity scale 2) were enrolled and followed up. A total of 175 cardiovascular events occurred during a median follow-up of 3.25 years (6.90 events per 1,000 person-month), comprising 133 cerebrovascular and 42 coronary artery events. The adjusted hazard ratio of diabetes was 1.50 (95% CI 1.08-2.10). In a multivariable Cox proportional hazards model, Malay and Indian ethnicities, BMI <23kg/m2 and a prior diagnosis of diabetes were identified as independent predictors of recurrent cardiovascular events. CONCLUSION: Our study provides quantitative data on the event rates of ischaemic stroke patients with diabetes. These findings provide insights on stroke predictors in a multi-ethnic Asian population, which may have implications in the design of future interventional studies.

Long-term effects of bariatric surgery on cardiovascular risk factors in Singapore.

INTRODUCTION: Bariatric surgery is considered an effective treatment for weight loss and for improving the metabolic profile of patients with obesity. Obesity-related comorbidities such as hyperlipidaemia and type 2 diabetes mellitus (DM) are significant cardiovascular risk factors. Additionally, prospective clinical trials have shown that statins increase the risk of development of DM, and many patients with obesity are on statins. We retrospectively examined the effect of bariatric surgery on lipid profile, DM control and weight loss at the five-year follow-up. METHODS: In total, 104 patients undergoing bariatric surgery from 2008 to 2012 were retrospectively studied. 36 patients were on preoperative statins. Their lipid profile, DM control and weight loss were examined at the one-year and five-year follow-ups. RESULTS: Both high-density lipoprotein and triglyceride levels showed significant improvement at the one-year and five-year follow-ups (p = 0.01). Total cholesterol showed significant improvement at the one-year follow-up (-0.30 mmol/dL, p = 0.0338); however, better control was not sustained at the five-year follow-up (-0.15 mmol/dL, p = 0.133). Low-density lipoprotein did not show any considerable improvement at the one- and five-year follow-ups (-0.27 mmol/dL, p = 0.150 and -0.24 mmol/dL, p = 0.138, respectively). A statistically significant improvement in DM control was observed in these patients and in those on preoperative statins. Weight loss was sustained at one and five years. CONCLUSION: Bariatric surgery does not confer a uniform improvement in lipid profile in the long term. It does, however, induce efficient weight loss and improvement in diabetic profile, even in patients on preoperative statins.

Evaluating the effectiveness of a multi-faceted inpatient diabetes management program among hospitalised patients with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is one of the most common chronic diseases. Individuals with DM are more likely to be hospitalised and stay longer than those without DM. Inpatient hypoglycemia and hyperglycemia, which are associated with adverse outcomes, are common, but can be prevented through hospital quality improvement programs. METHODS: We designed a multi-faceted intervention program with the aim of reducing inpatient hypoglycemia and hyperglycemia. This was implemented over seven phases between September 2013 to January 2016, and covered all the non-critical care wards in a tertiary hospital. The program represented a pragmatic approach that leveraged on existing resources and infrastructure within the hospital. We calculated glucometric outcomes in June to August 2016 and compared them with those in June to August 2013 to assess the overall effectiveness of the program. We used regression models with generalised estimating equations to adjust for potential confounders and account for correlations of repeated outcomes within patients and admissions. RESULTS: We observed significant reductions in patient-days affected by hypoglycemia (any glucose reading < 4 mmol/L: OR = 0.71, 95% CI: 0.61 to 0.83, p <  0.001), and hyperglycemia (any glucose reading > 14 mmol/L: OR = 0.84, 95% CI: 0.71 to 0.99, p = 0.041). Similar findings were observed for admission-level hypoglycemia and hyperglycemia. Further analyses suggested that these reductions started to occur four to 6 months post-implementation. CONCLUSIONS: Our program was associated with sustained improvements in clinically relevant outcomes. Our described intervention could be feasibly implemented by other secondary and tertiary care hospitals by leveraging on existing infrastructure and work force.

Effects of external counter-pulsation on endothelial function assessed by peripheral artery tonometry, levels of glycaemia and metabolic markers in individuals with type 2 diabetes mellitus.

BACKGROUND AND AIMS: External counter-pulsation (ECP) generates sheer stress thereby improving endothelial function and anginal symptoms in coronary artery disease. Endothelial dysfunction is also involved in the pathogenesis of T2DM. The aim of this pilot study was to investigate the use of ECP at different doses in improving endothelial function and glycaemic markers in T2DM. METHODS: This prospective study involved 46 subjects with T2DM randomly assigned to receive 35 sessions of ECP at different regimens (0.5 h versus 1 h) and duration (7 versus 12 weeks). Endothelial function was evaluated by reactive hyperaemia index (RHI) via peripheral arterial tonometry at the start, midpoint and end of study. Other secondary outcomes included fasting glucose, HOMA-IR, HbA1c, blood pressure, lipid profile, weight and vibration sense. RESULTS: There was no change in RHI across all 3 regimens of ECP individually or collectively at the end of the study (ΔRHI +0.01%, p = 0.458). Glycaemic markers also remained unchanged at endpoint. Subgroup analysis showed an improvement in RHI (ΔRHI +20.6%, p = 0.0178) in subjects with more severe endothelial dysfunction at baseline. CONCLUSION: ECP did not show a beneficial effect on endothelial function or glycemic control in this South-East Asian population with T2DM at any of the three regimens. This may partly be explained by less severe endothelial dysfunction and less insulin resistance in our population at baseline.

Fall Risk and Balance Confidence in Patients With Diabetic Peripheral Neuropathy: An Observational Study.

Objective: Individuals with diabetic peripheral neuropathy (DPN) have functional deficits that increase their risk of falling. However, psychological aspects such as loss of confidence in undertaking activities could also contribute to this risk. We examined correlations between balance confidence and fall risk among individuals with DPN. Methods: This was a cross-sectional study of 146 individuals with DPN. Elevated fall risk was determined by timed up-and-go test with standard cut-off time of 13.5 seconds, and balance confidence was measured by 16-item Activities Specific Balance Confidence scale. Functional parameters assessed included functional reach, body sway velocity during quiet standing and muscle strength at ankle and toe. Results: Twenty percent of the DPN patients were at increased risk of falls. Every unit increase in balance confidence was associated with 9% (95% confidence interval: 0.88, 0.95; p<0.001) reduced odds of falling, after adjusting for socio-demographic, health and functional characteristics. No other functional parameters had significant associations with fall risk in adjusted analyses. Conclusions: Psychological factors like balance confidence appear to be more important for fall risk among DPN patients, compared to objective functional performance. Interventions targeting balance confidence may be beneficial in reducing the risk of falls in this population.

Self-reported hypoglycaemia in insulin-treated patients with diabetes mellitus: results from the Singapore cohort of the International Operations Hypoglycaemia Assessment Tool study.

INTRODUCTION: Hypoglycaemia constitutes a significant barrier to achieving glycaemic control with insulin in both Type 1 (T1DM) and Type 2 diabetes mellitus (T2DM). The International Operations Hypoglycaemia Assessment Tool (IO HAT) study was designed to determine the incidence of hypoglycaemia in insulin-treated patients with T1DM and T2DM. METHODS: The IO HAT study retrospectively and prospectively assessed the incidence of hypoglycaemia in patients with insulin-treated diabetes mellitus in nine countries. This sub-analysis included patients from Singapore with T1DM or T2DM who were aged ≥ 21 years and had completed two self-assessment questionnaires (SAQ1 and SAQ2). RESULTS: Of the 50 T1DM and 320 T2DM patients who completed the SAQ1, 39 T1DM and 265 T2DM patients completed SAQ2; 100% and 90.9%, respectively, experienced at least one hypoglycaemic event prospectively. The incidence rates of any hypoglycaemia were 49.5 events per patient-year (EPPY) and 16.1 EPPY for T1DM and T2DM patients, respectively, in the four-week prospective period. Hypoglycaemia rate did not differ in terms of glycated haemoglobin level. The vast majority of T1DM or T2DM patients (92.0% and 90.7%, respectively) knew the overall definition of hypoglycaemia before study participation, although over half of the patients (T1DM 54.0%, T2DM 51.9%) defined hypoglycaemia based only on symptoms. CONCLUSION: High proportions of insulin-treated patients with diabetes mellitus in Singapore reported hypoglycaemic events prospectively, showing that they had underreported hypoglycaemic episodes retrospectively. Patient education can help in improving hypoglycaemia awareness and its management in the region.

Robust estimation of the effect of an exposure on the change in a continuous outcome.

BACKGROUND: The change in two measurements of a continuous outcome can be modelled directly with a linear regression model, or indirectly with a random effects model (REM) of the individual measurements. These methods are susceptible to model misspecifications, which are commonly addressed by applying monotonic transformations (e.g., Box-Cox transformation) to the outcomes. However, transforming the outcomes complicates the data analysis, especially when variable selection is involved. We propose a robust alternative through a novel application of the conditional probit (cprobit) model. METHODS: The cprobit model analyzes the ordered outcomes within each subject, making the estimate invariant to monotonic transformation on the outcome. By scaling the estimate from the cprobit model, we obtain the exposure effect on the change in the observed or Box-Cox transformed outcome, pending the adequacy of the normality assumption on the raw or transformed scale. RESULTS: Using simulated data, we demonstrated a similar good performance of the cprobit model and REM with and without transformation, except for some bias from both methods when the Box-Cox transformation was applied to scenarios with small sample size and strong effects. Only the cprobit model was robust to skewed subject-specific intercept terms when a Box-Cox transformation was used. Using two real datasets from the breast cancer and inpatient glycemic variability studies which utilize electronic medical records, we illustrated the application of our proposed robust approach as a seamless three-step workflow that facilitates the use of Box-Cox transformation to address non-normality with a common underlying model. CONCLUSIONS: The cprobit model provides a seamless and robust inference on the change in continuous outcomes, and its three-step workflow is implemented in an R package for easy accessibility.

Associations between health literacy and health care utilization and mortality in patients with coexisting diabetes and end-stage renal disease: A prospective cohort study.

Objectives Health literacy encompasses a broad skill set linked to patients' self-management ability and the complexity of their health care environments. Self-management in the context of multimorbidity is particularly challenging, placing patients at risk of poor clinical outcomes. This study aimed to explore the prognostic associations between health literacy domains, depression, and 12-month health care utilization and mortality in patients with diabetes and end-stage renal disease (DM-ESRD). Design Observational study. Methods Patients with DM-ESRD undergoing haemodialysis were recruited. Information on all-cause hospitalization/admission and mortality of participants was recorded. Negative binomial and Cox regressions were used to model risk factors for hospitalization and mortality. Results A total 221 participants [median age: 59 years, 61.6% men, 54.8% Chinese] were recruited. Differences in health literacy were found as a function of age, ethnicity, relationship status, and education. After adjusting for demographic and clinical factors, the HLQ domain Actively Managing My Health remained independently associated with lower rates of hospitalization (incidence rate ratio (IRR) = 0.674, 95% CI [0.490, 0.925], p = .02) and mortality (hazard ratio = 0.382, 95% CI [0.160, 0.848], p = .02). Cumulative hospitalization days were associated with employment status (IRR = 2.242, 95% CI [1.223, 4.113], p = .009), albumin (IRR = 0.918, 95% CI [0.854, 0.988], p = .02), HbA1c (IRR = 1.183, 95% CI [1.028, 1.360], p = .02), comorbidity burden (IRR = 1.137, 95% CI [1.003, 1.289], p = .04), and depression (IRR = 1.059, 95% CI [1.003, 1.118], p = .04) but no health literacy domains. Conclusions Health literacy skills related to Actively Managing My Health predict hospitalization and mortality independently of other risk factors. The HLQ provides an assessement of novel health literacy parameters which offer new insights into patients' status and behaviours and may strengthen interventions to improve clinical services, and patient outcomes in DM-ESRD. Statement of contribution What is already known on this subject? Patients with diabetes (DM) comprise the fastest growing segment of patients with end-stage renal disease (ESRD). Health literacy (HL) is pivotal for managing the complex treatment guidelines for DM-ESRD. Most prior work on HL focused on functional HL and shown significant associations with mortality and hospitalization. Limited research has investigated wider HL skills in relation to clinical outcomes. What does this study add? Supporting patients in Actively Managing my health liteacy skills is critical in decreasing probability of hospitalization and morbidity. The presence of symptoms of depression is associated with longer hospitalization period.

The effect of coffee consumption on insulin sensitivity and other biological risk factors for type 2 diabetes: a randomized placebo-controlled trial.

BACKGROUND: In observational studies, coffee consumption has been consistently associated with a lower risk of type 2 diabetes mellitus. Trials examining the effect of coffee consumption on glucose metabolism have been limited by the use of surrogate insulin sensitivity indices, small sample sizes, lack of blinding, and short follow-up duration. OBJECTIVES: We aimed to overcome limitations of previously conducted coffee trials in a randomized placebo-controlled trial of the effect of coffee consumption on insulin sensitivity. METHODS: We conducted a 24-wk randomized placebo-controlled trial in 126 overweight, non-insulin sensitive (HOMA-IR ≥1.30), Chinese, Malay, and Asian-Indian males and females aged 35-69 y. Participants were randomly assigned to receive 4 cups of instant regular coffee (n = 62) or 4 cups of a coffee-like placebo beverage (n = 64) per day. The primary outcome was the amount of glucose metabolized per kilogram of body weight per minute (Mbw) assessed during steady-state conditions with a hyperinsulinemic euglycemic clamp. Secondary outcomes included other clamp-based insulin sensitivity measures, biological mediators of insulin sensitivity, and measures of fasting glucose metabolism. RESULTS: Coffee consumption did not significantly change insulin sensitivity compared with placebo (percentage mean difference in Mbw = 4.0%; 95% CI: -8.3, 18.0%; P = 0.53). Furthermore, no significant differences in fasting plasma glucose (2.9%; 95% CI: -0.4, 6.3%; P = 0.09) or biological mediators of insulin resistance, such as plasma adiponectin (2.3%; 95% CI: -1.4, 6.2%; P = 0.22), were observed between coffee and placebo groups over 24 wk of intervention. Participants in the coffee arm experienced a loss of fat mass (FM) (-3.7%; 95% CI: -6.3, -1.1%; P = 0.006) and reduction in urinary creatinine concentrations (-21.2%; 95% CI: -31.4, -9.5%; P = 0.001) compared with participants in the placebo arm over 24 wk of intervention. CONCLUSIONS: Consuming 4 cups/d of caffeinated coffee for 24 wk had no significant effect on insulin sensitivity or biological mediators of insulin resistance but was associated with a modest loss of FM and reduction in urinary creatinine concentrations.This trial was registered at clinicaltrials.gov as NCT01738399. Registered on November 28, 2012. Trial sponsor: Nestlé Research, Lausanne, Switzerland. Trial site: National University of Singapore.

Handling ties in continuous outcomes for confounder adjustment with rank-ordered logit and its application to ordinal outcomes.

The rank-ordered logit (rologit) model was recently introduced as a robust approach for analysing continuous outcomes, with the linear exposure effect estimated by scaling the rank-based log-odds estimate. Here we extend the application of the rologit model to continuous outcomes with ties and ordinal outcomes treated as imperfectly-observed continuous outcomes. By identifying the functional relationship between survival times and continuous outcomes, we explicitly establish the equivalence between the rologit and Cox models to justify the use of the Breslow, Efron and perturbation methods in the analysis of continuous outcomes with ties. Using simulation, we found all three methods perform well with few ties. Although an increasing extent of ties increased the bias of the log-odds and linear effect estimates and resulted in reduced power, which was somewhat worse when the model was mis-specified, the perturbation method maintained a type I error around 5%, while the Efron method became conservative with heavy ties but outperformed Breslow. In general, the perturbation method had the highest power, followed by the Efron and then the Breslow method. We applied our approach to three real-life datasets, demonstrating a seamless analytical workflow that uses stratification for confounder adjustment in studies of continuous and ordinal outcomes.

Altered Motor and Motor Perceptual Cognitive Imagery Task-Related Activation in Diabetic Peripheral Neuropathy: Insights From Functional MRI.

OBJECTIVE: To compare central nervous system (CNS) activation in patients with and without diabetic peripheral neuropathy (DPN) during motor and motor imagery tasks and to correlate activation with functional performance. RESEARCH DESIGN AND METHODS: Twenty-six participants (13 with DPN, 13 without DPN) underwent functional MRI during three tasks: ankle dorsi plantar flexion (motor task [MT]) and motor imagery tasks of walking on a smooth surface (SMIT) and rough surface (RMIT). Functional assessment included gait analysis, ankle muscle strength, and ankle range of motion. RESULTS: The tasks activated the sensorimotor, motor preparation, visual processing, and decision-making regions. Activation was significantly lower in patients with DPN than in those without DPN during MT and SMIT but not RMIT. Poor functional performance in patients with DPN was associated with greater activation in motor preparation regions. CONCLUSIONS: In patients with DPN, CNS responses appear muted compared with patients without DPN, but they remain capable of enhancing CNS activation when tasks are more challenging or when functional deficits are substantial.

Short-term strength and balance training does not improve quality of life but improves functional status in individuals with diabetic peripheral neuropathy: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to test the effectiveness of a structured strength and balance training intervention in improving health-related quality of life (HRQoL) and functional status in individuals with diabetic peripheral neuropathy (DPN). METHODS: The study was a single-blind parallel-group randomised controlled trial comparing 2 months of once-weekly home-based strength and balance training against standard medical therapy. Participants were patients with physician-diagnosed type 2 diabetes and neuropathy recruited from five public sector institutions in Singapore between July 2014 and October 2017. Participants were block-randomised to intervention or control arms. Outcomes were assessed at baseline, 2 months and 6 months by a trained assessor blinded to group assignment. Primary outcomes were change in physical component summary (PCS) score of SF-36v2 (a 36-item generic HRQoL instrument that has been validated for use in Singapore) and EQ-5D-5L index score (derived from a five-item generic HRQoL instrument [EQ-5D-5L]) over 6 months. Secondary outcomes were change in functional status (timed up-and-go [TUG], five times sit-to-stand [FTSTS], functional reach, static balance, ankle muscle strength and knee range of motion) and balance confidence over 6 months. Mean differences in scores between groups were compared using mixed models. RESULTS: Of the 143 participants randomised (intervention, n = 70; control, n = 73), 67 participants were included in each arm for the final intention-to-treat analysis. The two groups were similar, except in terms of sex. There were no significant differences between groups on the primary outcomes of PCS score (mean difference [MD] 1.56 [95% CI -1.75, 4.87]; p = 0.355) and EQ-5D-5L index score (MD 0.02 [95% CI -0.01, 0.06]; p = 0.175). There were significant improvements in TUG test performance (MD -1.14 [95% CI -2.18, -0.1] s; p = 0.032), FTSTS test performance (MD -1.31 [95% CI -2.12, -0.51] s; p = 0.001), ankle muscle strength (MD 4.18 [95% CI 0.4, 7.92] N; p = 0.031), knee range of motion (MD 6.82 [95% CI 2.87, 10.78]°; p = 0.001) and balance confidence score (MD 6.17 [95% CI 1.89, 10.44]; p = 0.005). No adverse events due to study participation or study intervention were reported. CONCLUSIONS/INTERPRETATION: Short-term structured strength and balance training did not influence HRQoL but produced sustained improvements in functional status and balance confidence at 6 months. More intensive interventions may be needed to influence HRQoL in these individuals. However, this intervention may be a useful treatment option for individuals with DPN to reduce the risk of falls and injuries. TRIAL REGISTRATION: ClinicalTrials.gov NCT02115932 FUNDING: This work was supported by the National Medical Research Council, Singapore.

Using marginal standardisation to estimate relative risk without dichotomising continuous outcomes.

BACKGROUND: Although criticisms regarding the dichotomisation of continuous variables are well known, applying logit model to dichotomised outcomes is the convention because the odds ratios are easily obtained and they approximate the relative risks (RRs) for rare events. METHODS: To avoid dichotomisation when estimating RR, the marginal standardisation method that transforms estimates from logit or probit model to RR estimate is extended to include estimates from linear model in the transformation. We conducted a simulation study to compare the statistical properties of the estimates from: (i) marginal standardisation method between models for continuous (i.e., linear model) and dichotomised outcomes (i.e., logit or probit model), and (ii) marginal standardisation method and distributional approach (i.e., marginal mean method) applied to linear model. We also compared the diagnostic test for probit, logit and linear models. For the real dataset analysis, we applied these analytical approaches to assess the management of inpatient hyperglycaemia in a pilot intervention study. RESULTS: Although the RR estimates from the marginal standardisation method were generally unbiased for all models in the simulation study, the marginal standardisation method for linear model provided estimates with higher precision and power than logit or probit model, especially when the baseline risks were at the extremes. When comparing approaches that avoid dichotomisation, RR estimates from these approaches had comparable performance. Assessing the assumption of error distribution was less powerful for logit or probit model via link test when compared with diagnostic test for linear model. After accounting for multiple thresholds representing varying levels of severity in hyperglycaemia, marginal standardisation method for linear model provided stronger evidence of reduced hyperglycaemia risk after intervention in the real dataset analysis although the RR estimates were similar across various approaches. CONCLUSIONS: When compared with approaches that do not avoid dichotomisation, the RR estimated from linear model is more precise and powerful, and the diagnostic test from linear model is more powerful in detecting mis-specified error distributional assumption than the diagnostic test from logit or probit model. Our work describes and assesses the methods available to analyse data involving studies of continuous outcomes with binary representations.

Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence.

BACKGROUND: Sphingolipids (SPs) are ubiquitous, structurally diverse molecules that include ceramides, sphingomyelins, and sphingosines. They are involved in various pathologies including obesity and type 2 diabetes mellitus (T2DM). Therefore, it is likely that perturbations in plasma concentrations of SPs are associated with disease. Identifying these associations may reveal useful biomarkers or provide insight into disease processes. METHODS: We performed a lipidomics evaluation of molecularly-distinct SPs in the plasma of 2,302 ethnically-Chinese Singaporeans using electrospray ionization mass spectrometry coupled with liquid chromatography. SP profiles were compared to clinical and biochemical characteristics, and subjects were evaluated by follow-up visits for 11 years. RESULTS: We found that ceramides correlate positively but hexosylceramides correlate negatively with body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, SPs with a d16:1 sphingoid backbone correlate more positively with BMI and HOMA-IR, while d18:2 SPs correlate less positively, relative to canonical d18:1 SPs. We also found that higher concentrations of two distinct sphingomyelins were associated with a higher risk of T2DM (HR 1.45, 95% CI 1.18-1.78 for SM d16:1/C18:0; and HR 1.40, 95% CI 1.17-1.68 for SM d18:1/C18:0). CONCLUSION: We identified significant associations between SPs and obesity/T2DM characteristics, specifically, that of hexosylceramides, d16:1 SPs, and d18:2 SPs. This suggests that the balance of SP metabolism, rather than ceramide accumulation, is associated with the pathology of obesity. We further identified two specific SPs that may represent prognostic biomarkers for T2DM. FUNDING: Funding sources are listed in the Acknowledgements section.

Measurement equivalence of the English, Chinese and Malay versions of the World Health Organization quality of life (WHOQOL-BREF) questionnaires.

BACKGROUND: The WHOQOL-BREF is a widely used questionnaire for measuring quality of life. It is important to establish the measurement equivalence of various language versions of WHOQOL-BREF so that scores from different language versions may be pooled together. The primary aim of this article was to evaluate the measurement equivalence of the English, Chinese and Malay versions of the WHOQOL-BREF. METHODS: We analysed data from the previously published, cross-sectional, WONDERS study and used linear regression models to adjust for potential confounding variables. Based on equivalence clinical trial methods, measurement equivalence was assessed by comparing 90% confidence interval (CI) of differences in scores across language versions with a predefined equivalence margin of 0.3 SD. Equivalence was achieved if the 90% CI fell within 0.3 SD. Data from 1203 participants, aged above 21 years, were analysed. RESULTS: Participants who completed the different language versions of WHOQOL-BREF expectedly differed in age, ethnicity, highest education level, marital status, smoking status and Body Mass Index (BMI). The English and Malay language versions were definitely equivalent for all domains. The English and Chinese language versions were definitely equivalent for physical and environmental domains but inconclusive for psychological and social domains. Likewise, for Chinese and Malay versions. CONCLUSION: The English, Chinese and Malay language versions of the WHOQOL-BREF questionnaire may be considered equivalent, with evidence being more robust for some domains than the others. Given the large number of people who speak/ read Chinese and Malay, this study has widespread relevance.