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BACKGROUND: Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. METHODS: This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. RESULTS: This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [- 8.4% (- 18.6, 3.2), p = 0.150, and - 4.6% (- 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [- 1.6% (- 2.9, - 0.2), p = 0.021] but not troponin I concentrations [- 1.5% (- 4.2, 1.2), p = 0.263]. CONCLUSIONS: In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinic

Contains fulltext : 235311.pdf (Publisher’s version ) (Open Access), BACKGROUND: Closed-loop insulin delivery systems, which integrate continuous glucose monitoring (CGM) and algorithms that continuously guide insulin dosing, have been shown to improve glycaemic control. The ability to predict future glucose values can further optimize such devices. In this study, we used machine learning to train models in predicting future glucose levels based on prior CGM and accelerometry data. METHODS: We used data from The Maastricht Study, an observational population-based cohort that comprises individuals with normal glucose metabolism, prediabetes, or type 2 diabetes. We included individuals who underwent >48h of CGM (n = 851), most of whom (n = 540) simultaneously wore an accelerometer to assess physical activity. A random subset of individuals was used to train models in predicting glucose levels at 15- and 60-minute intervals based on either CGM data or both CGM and accelerometer data. In the remaining individuals, model performance was evaluated with root-mean-square error (RMSE), Spearman's correlation coefficient (rho) and surveillance error grid. For a proof-of-concept translation, CGM-based prediction models were optimized and validated with the use of data from individuals with type 1 diabetes (OhioT1DM Dataset, n = 6). RESULTS: Models trained with CGM data were able to accurately predict glucose values at 15 (RMSE: 0.19mmol/L; rho: 0.96) and 60 minutes (RMSE: 0.59mmol/L, rho: 0.72). Model performance was comparable in individuals with type 2 diabetes. Incorporation of accelerometer data only slightly improved prediction. The error grid results indicated that model predictions were clinically safe (15 min: >99%, 60 min >98%). Our prediction models translated well to individuals with type 1 diabetes, which is reflected by high accuracy (RMSEs for 15 and 60 minutes of 0.43 and 1.73 mmol/L, respectively) and clinical safety (15 min: >99%, 60 min: >91%). CONCLUSIONS: Machine learning-based models are able to accurately and safely predic

Contains fulltext : 229316.pdf (Publisher’s version ) (Open Access)

Low-flow extracorporeal life support can be used for cardiopulmonary support of paediatric and neonatal patients and is also emerging as a therapy for patients suffering from exacerbation of chronic obstructive pulmonary disease. However, pump heating and haemolysis have proven to negatively affect the system and outcome. This in vitro study aimed at gaining insight into blood warming, pump heating and haemolysis related to the performance of a new low-flow centrifugal pump. Pump performance in the 400-1,500 ml/min flow range was modulated using small-sized dual-lumen catheters and freshly donated human blood. Measurements included plasma free haemoglobin, blood temperature, pump speed, pump pressure, blood flow and thermographic imaging. Blood warming (T-max=0.5 degrees C) had no relationship with pump performance or haemolysis (R-max(2)=0.05). Pump performance-related parameters revealed no relevant relationships with haemolysis (R-max(2)=0.36). Thermography showed no relevant heat zones in the pump (T-max=36 degrees C). Concerning blood warming, pump heating and haemolysis, we deem the centrifugal pump applicable for low-flow extracorporeal circulation.

Item does not contain fulltext, Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-alpha G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-alpha G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p<0.001) improved, while 30.3% (10 out of 33) of variant A-allele carriers responded favourably to TNF inhibitors. For patients with the GG-genotype, the probability of improving compared with remaining stable or deteriorating was three times higher (risk ratio 3.09, 95% CI 1.84-5.20). Sarcoidosis patients without the TNF-alpha -308A variant allele (GG-genotype) had a three-fold higher response to TNF inhibitors (adalimumab or infliximab). Further research is needed to evaluate the value of genotyping for the TNF-alpha G-308A polymorphism in order to tailor TNF-inhibitor treatment.

Purinergic receptors are important for the regulation of inflammation, muscle contraction, neurotransmission and nociception. Extracellular ATP and its metabolites are the main ligands for these receptors. Occasional reports on beneficial results of ATP administration in human and animal studies have suggested the bioavailability of oral ATP supplements. We investigated whether prolonged daily intake of oral ATP is indeed bioavailable. Thirty-two healthy subjects were randomised to receive 0, 250, 1250 or 5000 mg ATP per d for 28 d by means of enteric-coated pellets. In addition, on days 0 and 28, all thirty-two subjects received 5000 mg ATP to determine whether prolonged administration would induce adaptations in the bioavailability of ATP. ATP supplementation for 4 weeks did not lead to changes in blood or plasma ATP concentrations. Of all ATP metabolites, only plasma uric acid levels increased significantly after the administration of 5000 mg of ATP. Prolonged administration of ATP was safe as evidenced from liver and kidney parameters. We conclude that oral administration of ATP only resulted in increased uric acid concentrations. On the basis of these findings, we seriously question the claimed efficacy of oral ATP at dosages even lower than that used in the present study.

Chorioamnionitis frequently induces a fetal inflammatory response syndrome (FIRS), characterized by an elevation of pro-inflammatory mediators and systemic inflammation. Although there is increasing evidence that inflammation and lipid metabolism influence each other, the effects of chorioamnionitis-induced FIRS on fetal lipid homeostasis are currently not known. Accordingly, we hypothesize that chorioamnionitis induces an inflammatory response in the fetal liver, consequently leading to metabolic disturbances. Chorioamnionitis was induced by intra-amniotic injection of 10 mg endotoxin (control) two days or two weeks before delivery. Saline injections were given to controls. The effect of chorioamnionitis on hepatic inflammation and metabolic parameters was analyzed in ovine fetuses at the gestational age (GA) of 125 days (normal GA= 150 days). We found that two days after the endotoxin injections, inflammatory markers were significantly higher compared to controls. Additionally, lipid and glucose metabolism were disturbed in response to endotoxin. Moreover, the anti-oxidant state capacity was reduced and hepatic damage was apparent. Two weeks after the endotoxin injections the fetal livers were still inflamed and had higher glucose concentrations in the blood. In addition, the levels of markers for hepatic damage (ALT, AST) were elevated. In conclusion, chorioamnionitis induces liver inflammation, leading to metabolic disturbances in the fetus. ABBREVIATIONS

BACKGROUND: Memory problems are a main feature of mild cognitive impairment (MCI) and may be related to the apolipoprotein E (APOE) epsilon4 allele. We investigated whether the effect of the APOE genotype on memory in subjects with MCI was dependent on age and underlying Alzheimer disease (AD) pathology. METHODS: Subjects with MCI (n = 180) were selected from a memory clinic setting. Subjects with at least one APOE epsilon4 allele (n = 83) were compared to non-carriers on several memory measures. Subjects were reassessed 5-10 years later in order to identify those who developed AD. RESULTS: In the middle-aged subgroup, the APOE epsilon4 allele was most strongly related to decreased subjective organization and in the old subgroup to a decreased delayed recall. After excluding subjects with incipient AD (n = 33), results remained similar in the middle-aged subgroup, but in the old subgroup the APOE genotype was no longer associated with memory dysfunction. CONCLUSION: The presence of the APOE epsilon4 allele is associated with impaired memory functioning in both middle-aged and old subjects with MCI, although the memory function affected varies with age. Its effect on memory function may be dependent on underlying AD pathology in elderly subjects, but not in middle-aged subjects.