OBJECTIVEAutophagy is a critical cellular system for removal of aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in the development of heart failure, the role of autophagy in the development of diabetic cardiomyopathy has not been studied. We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice.RESEARCH DESIGN AND METHODSOVE26 mice and cardiac-specific AMPK dominant negative transgenic (DN)-AMPK diabetic mice were treated with metformin or vehicle for 4 months, and cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.RESULTSCompared with control mice, diabetic OVE26 mice exhibited a significant reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 mouse hearts exhibited aggregation of chaotically distributed mitochondria between poorly organized myofibrils and increased polyubiquitinated protein and apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and increased mortality in diabetic mice. Finally, chronic metformin therapy significantly enhanced autophagic activity and preserved cardiac functions in diabetic OVE26 mice but not in DN-AMPK diabetic mice.CONCLUSIONSDecreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy. Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may represent a novel approach to treat diabetic cardiomyopathy.

OnabotulinumtoxinA has been shown to reduce the frequency of headaches in patients with chronic migraine and can be considered a cost-effective use of resources in the UK National Health Service. The uncertainties in the model relate to the extrapolation of clinical data beyond the 56-week trial.

Background Ultrasonography has been the mainstay of antenatal screening programmes in the UK for many years. Technical factors and physical limitations may result in suboptimal images that can lead to incorrect diagnoses and inaccurate counselling and prognostic information being given to parents. Previous studies suggest that the addition of in utero magnetic resonance imaging (iuMRI) may improve diagnostic accuracy for fetal brain abnormalities. These studies have limitations, including a lack of an outcome reference diagnosis (ORD), which means that improvements could not be assessed accurately. Objectives To assess the diagnostic impact, acceptability and cost consequence of iuMRI among fetuses with a suspected fetal brain abnormality. Design A pragmatic, prospective, multicentre, cohort study with a health economics analysis and a sociological substudy. Setting Sixteen UK fetal medicine centres. Participants Pregnant women aged ≥ 16 years carrying a fetus (at least 18 weeks’ gestation) with a suspected brain abnormality detected on ultrasonography. Interventions Participants underwent iuMRI and the findings were reported to their referring fetal medicine clinician. Main outcome measures Pregnancy outcome was followed up and an ORD from postnatal imaging or postmortem autopsy/imaging collected when available. Developmental data from the Bayley Scales of Infant Development and questionnaires were collected from the surviving infants aged 2–3 years. Data on the management of the pregnancy before and after the iuMRI were collected to inform the economic evaluation. Two surveys collected data on patient acceptability of iuMRI and qualitative interviews with participants and health professionals were undertaken. Results The primary analysis consisted of 570 fetuses. The absolute diagnostic accuracies of ultrasonography and iuMRI were 68% and 93%, respectively [a difference of 25%, 95% confidence interval (CI) 21% to 29%]. The difference between ultrasonography and iuMRI increased with gestational age. In the 18–23 weeks group, the figures were 70% for ultrasonography and 92% for iuMRI (difference of 23%, 95% CI 18% to 27%); in the ≥ 24 weeks group, the figures were 65% for ultrasonography and 94% for iuMRI (difference of 29%, 95% CI 23% to 36%). Patient acceptability was high, with at least 95% of respondents stating that they would have iuMRI again in a similar situation. Health professional interviews suggested that iuMRI was acceptable to clinicians and that iuMRI was useful as an adjunct to ultrasonography, but not as a replacement. Across a range of scenarios, iuMRI resulted in additional costs compared with ultrasonography alone. The additional cost was consistently < £600 per patient and the cost per management decision appropriately changed was always < £3000. There is potential for reporting bias from the referring clinicians on the diagnostic and prognostic outcomes. Lower than anticipated follow-up rates at 3 years of age were observed. Conclusions iuMRI as an adjunct to ultrasonography significantly improves the diagnostic accuracy and confidence for the detection of fetal brain abnormalities. An evaluation of the use of iuMRI for cases of isolated microcephaly and the diagnosis of fetal spine abnormalities is recommended. Longer-term follow-up studies of children diagnosed with fetal brain abnormalities are required to fully assess the functional significance of the diagnoses. Trial registration Current Controlled Trials ISRCTN27626961. 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. 23, No. 49. See the NIHR Journals Library website for further project information.

This review examined the psychometric performance of 4 generic child-and adolescent-specific preference-based measures that can be used to produce utilities for child and adolescent health. Methods: A systematic search was undertaken to identify studies reporting the psychometric performance of the Child Health Utility (CHU9D), EQ-5D-Y (3L or 5L), and Health Utilities Index Mark 2 (HUI2) or Mark 3 (HUI3) in children and/or adolescents. Data were extracted to assess known-group validity, convergent validity, responsiveness, reliability, acceptability, and feasibility. Data were extracted separately for the dimensions and utility index where this was reported. Results: The review included 76 studies (CHU9D n = 12, EQ-5D-Y-3L n = 20, HUI2 n = 26,HUI3 n = 43), which varied considerably across conditions and sample size. EQ-5D-Y-3L had the largest amount of evidence of good psychometric performance in proportion to the number of studies examining performance. The majority of the evidence related to EQ-5D-Y-3L was based on dimensions. CHU9D was assessed in fewer studies, but the majority of studies found evidence of good psychometric performance. Evidence for HUI2 and HUI3 was more mixed, but the studies were more limited in sample size and statistical power, which was likely to have affected performance. Conclusions: The heterogeneity of published studies means that the evidence is based on studies across a range of countries, populations and conditions, using different study designs, different languages, different value sets and different statistical techniques. Evidence for CHU9D in particular is based on a limited number of studies. The findings raise concerns about the comparability of self-report and proxy-report responses to generate utility values for children and adolescents.