Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Randomised controlled trial and economic analysis of an internet-based weight management programme: POWeR+ (Positive Online Weight Reduction).

BACKGROUND: Behavioural counselling with intensive follow-up for obesity is effective, but in resource-constrained primary care settings briefer approaches are needed. OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of an internet-based behavioural intervention with regular face-to-face or remote support in primary care, compared with brief advice. DESIGN: Individually randomised three-arm parallel trial with health economic evaluation and nested qualitative interviews. SETTING: Primary care general practices in the UK. PARTICIPANTS: Patients with a body mass index of ≥ 30 kg/m2 (or ≥ 28 kg/m2 with risk factors) identified from general practice records, recruited by postal invitation. INTERVENTIONS: Positive Online Weight Reduction (POWeR+) is a 24-session, web-based weight management intervention completed over 6 months. Following online registration, the website randomly allocated participants using computer-generated random numbers to (1) the control intervention (n = 279), which had previously been demonstrated to be clinically effective (brief web-based information that minimised pressure to cut down foods, instead encouraging swaps to healthier choices and increasing fruit and vegetables, plus 6-monthly nurse weighing); (2) POWeR+F (n = 269), POWeR+ supplemented by face-to-face nurse support (up to seven contacts); or (3) POWeR+R (n = 270), POWeR+ supplemented by remote nurse support (up to five e-mails or brief telephone calls). MAIN OUTCOME MEASURES: The primary outcome was a modelled estimate of average weight reduction over 12 months, assessed blind to group where possible, using multiple imputation for missing data. The secondary outcome was the number of participants maintaining a 5% weight reduction at 12 months. RESULTS: A total of 818 eligible individuals were randomised using computer-generated random numbers. Weight change, averaged over 12 months, was documented in 666 out of 818 participants (81%; control, n = 227; POWeR+F, n = 221; POWeR+R, n = 218). The control group maintained nearly 3 kg of weight loss per person (mean weight per person: baseline, 104.4 kg; 6 months, 101.9 kg; 12 months, 101.7 kg). Compared with the control group, the estimated additional weight reduction with POWeR+F was 1.5 kg [95% confidence interval (CI) 0.6 to 2.4 kg; p = 0.001] and with POWeR+R was 1.3 kg (95% CI 0.34 to 2.2 kg; p = 0.007). By 12 months the mean weight loss was not statistically significantly different between groups, but 20.8% of control participants, 29.2% of POWeR+F participants (risk ratio 1.56, 95% CI 0.96 to 2.51; p = 0.070) and 32.4% of POWeR+R participants (risk ratio 1.82, 95% CI 1.31 to 2.74; p = 0.004) maintained a clinically significant 5% weight reduction. The POWeR+R group had fewer individuals who reported doing another activity to help lose weight [control, 47.1% (64/136); POWeR+F, 37.2% (51/137); POWeR+R, 26.7% (40/150)]. The incremental cost to the health service per kilogram weight lost, compared with the control group, was £18 (95% CI -£129 to £195) for POWeR+F and -£25 (95% CI -£268 to £157) for POWeR+R. The probability of being cost-effective at a threshold of £100 per kilogram was 88% and 98% for POWeR+F and POWeR+R, respectively. POWeR+R was dominant compared with the control group. No harms were reported and participants using POWeR+ felt more enabled in managing their weight. The qualitative studies documented that POWeR+ was viewed positively by patients and that health-care professionals generally enjoyed supporting patients using POWeR+. STUDY LIMITATIONS: Maintenance of weight loss after 1 year is unknown. FUTURE WORK: Identifying strategies for longer-term engagement, impact in community settings and increasing physical activity. CONCLUSION: Clinically valuable weight loss (> 5%) is maintained in 20% of individuals using novel written materials with brief follow-up. A web-based behavioural programme and brief support results in greater mean weight loss and 10% more participants maintain valuable weight loss; it achieves greater enablement and fewer participants undertaking other weight-loss activities; and it is likely to be cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21244703. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 4. See the NIHR Journals Library website for further project information.

A Bayesian network for modelling blood glucose concentration and exercise in type 1 diabetes.

This article presents a new statistical approach to analysing the effects of everyday physical activity on blood glucose concentration in people with type 1 diabetes. A physiologically based model of blood glucose dynamics is developed to cope with frequently sampled data on food, insulin and habitual physical activity; the model is then converted to a Bayesian network to account for measurement error and variability in the physiological processes. A simulation study is conducted to determine the feasibility of using Markov chain Monte Carlo methods for simultaneous estimation of all model parameters and prediction of blood glucose concentration. Although there are problems with parameter identification in a minority of cases, most parameters can be estimated without bias. Predictive performance is unaffected by parameter misspecification and is insensitive to misleading prior distributions. This article highlights important practical and theoretical issues not previously addressed in the quest for an artificial pancreas as treatment for type 1 diabetes. The proposed methods represent a new paradigm for analysis of deterministic mathematical models of blood glucose concentration.

The reduced cost of providing a nationally recognised service for familial hypercholesterolaemia.

OBJECTIVE: Familial hypercholesterolaemia (FH) affects 1 in 500 people in the UK population and is associated with premature morbidity and mortality from coronary heart disease. In 2008, National Institute for Health and Care Excellence (NICE) recommended genetic testing of potential FH index cases and cascade testing of their relatives. Commissioners have been slow to respond although there is strong evidence of cost and clinical effectiveness. Our study quantifies the recent reduced cost of providing a FH service using generic atorvastatin and compares NICE costing estimates with three suggested alternative models of care (a specialist-led service, a dual model service where general practitioners (GPs) can access specialist advice, and a GP-led service). METHODS: Revision of existing 3 year costing template provided by NICE for FH services, and prediction of costs for running a programme over 10 years. Costs were modelled for the first population-based FH service in England which covers Southampton, Hampshire, Isle of Wight and Portsmouth (SHIP). Population 1.95 million. RESULTS: With expiry of the Lipitor (Pfizer atorvastatin) patent the cost of providing a 10-year FH service in SHIP reduces by 42.5% (£4.88 million on patent vs £2.80 million off patent). Further cost reductions are possible as a result of the reduced cost of DNA testing, more management in general practice, and lower referral rates to specialists. For instance a dual-care model with GP management of patients supported by specialist advice when required, costs £1.89 million. CONCLUSIONS: The three alternative models of care are now <50% of the cost of the original estimates undertaken by NICE.

Daily energy expenditure, cardiorespiratory fitness and glycaemic control in people with type 1 diabetes.

OBJECTIVE: Encouraging daily physical activity improves cardiorespiratory fitness and many cardiovascular risk factors. However, increasing physical activity often creates a challenge for people with type 1 diabetes, because of difficulties maintaining euglycemia in the face of altered food intake and adjustments to insulin doses. Our aim was to examine the triangular relationship between glucose control measured by continuous glucose monitoring system (CGMS), objective measures of total daily energy expenditure (TEE) recorded by a multi-sensory monitoring device, and cardiorespiratory fitness (CRF), in free-living subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-three individuals (12 women) with type 1 diabetes who were free from micro- and macrovascular complications were recruited. TEE and glucose control were monitored simultaneously for up to 12 days, using a multi-sensory device and CGMS respectively. CRF was recorded as V02 max from a maximal treadmill test with the Bruce protocol. RESULTS: Subjects (mean±SD) were aged 37±11 years, with BMI = 26.5±5.1 kg.m⁻², HbA1c = 7.7±1.3% (61±14 mmol/mol) and V02 max (ml.min⁻¹.kg⁻¹)  = 39.9±8.4 (range 22.4-58.6). TEE (36.3±5.5 kcal.kg⁻¹.day⁻¹) was strongly associated with CRF(39.9±8.4 ml.min⁻¹.kg⁻¹) independently of sex (r = 0.63, p<0.01). However, neither TEE (r = -0.20, p = 0.36) nor CRF (r = -0.20, p = 0.39; adjusted for sex), were significantly associated with mean glycaemia measured by CGMS. CONCLUSION: Higher levels of energy expenditure (due to a more active lifestyle) are associated with increased cardiorespiratory fitness, but not necessarily better glycaemic control. Since increased levels of energy expenditure and good glycaemic control are both needed to protect against diabetes-related complications our data suggest they need to be achieved independently.

Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?

Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease.