Are glucose profiles well-controlled within the targets recommended by the International Diabetes Federation in type 2 diabetes? A meta-analysis of results from continuous glucose monitoring based studies

AIMS: To assess continuous glucose monitoring (CGM) derived intra-day glucose profiles using global guideline for type 2 diabetes recommended by the International Diabetes Federation (IDF). METHODS: The Cochrane Library, MEDLINE, PubMed, CINAHL and Science Direct were searched to identify observational studies reporting intra-day glucose profiles using CGM in people with type 2 diabetes on any anti-diabetes agents. Overall and subgroup analyses were conducted to summarise mean differences between reported glucose profiles (fasting glucose, pre-meal glucose, postprandial glucose and post-meal glucose spike/excursion) and the IDF targets. RESULTS: Twelve observational studies totalling 731 people were included. Pooled fasting glucose (0.81 mmol/L, 95% CI, 0.53-1.09 mmol/L), postprandial glucose after breakfast (1.63 mmol/L, 95% CI, 0.79-2.48 mmol/L) and post-breakfast glucose spike (1.05 mmol/L, 95% CI, 0.13-1.96 mmol/L) were significantly higher than the IDF targets. Pre-lunch glucose, pre-dinner glucose and postprandial glucose after lunch and dinner were above the IDF targets but not significantly. Subgroup analysis showed significantly higher fasting glucose and postprandial glucose after breakfast in all groups: HbA1c <7% and ≥7% (53 mmol/mol) and duration of diabetes <10 years and ≥10 years. CONCLUSIONS: Independent of HbA1c, fasting glucose and postprandial glucose after breakfast are not well-controlled in type 2 diabetes

Dose-response between frequency of breaks in sedentary time and glucose control in type 2 diabetes: a proof of concept study

Objectives This study aimed to investigate dose-response between frequency of breaks in sedentary time and glucose control.DesignRandomised three-treatment, two-period balanced incomplete block trial.MethodsTwelve adults with type 2 diabetes (age, 60 ± 11 years; body mass index, 30.2 ± 4.7 kg/m2) participated in two of the following treatment conditions: sitting for 7 h interrupted by 3 min light-intensity walking breaks every (1) 60 min (Condition 1), (2) 30 min (Condition 2), and (3) 15 min (Condition 3). Postprandial glucose incremental area under the curves (iAUCs) and 21-h glucose total area under the curve (AUC) were measured using continuous glucose monitoring. Standardised meals were provided. Results Compared with Condition 1 (6.7 ± 0.8 mmol L−1 × 3.5 h−1), post-breakfast glucose iAUC was reduced for Condition 3 (3.5 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.04). Post-lunch glucose iAUC was lower in Condition 3 (1.3 ± 0.9 mmol L−1 × 3.5 h−1, p ˂ 0.03) and Condition 2 (2.1 ± 0.7 mmol L−1 × 3.5 h−1, p ˂ 0.05) relative to Condition 1 (4.6 ± 0.8 mmol L−1 × 3.5 h−1). Condition 3 (1.0 ± 0.7 mmol L−1 × 3.5 h−1, p = 0.02) and Condition 2 (1.6 ± 0.6 mmol L−1 × 3.5 h−1, p ˂ 0.04) attenuated post-dinner glucose iAUC compared with Condition 1 (4.0 ± 0.7 mmol L−1 × 3.5 h−1). Cumulative 10.5-h postprandial glucose iAUC was lower in Condition 3 than Condition 1 (p = 0.02). Condition 3 reduced 21-h glucose AUC compared with Condition 1 (p < 0.001) and Condition 2 (p = 0.002). However, post-breakfast glucose iAUC, cumulative 10.5-h postprandial glucose iAUC and 21-h glucose AUC were not different between Condition 2 and Condition 1 (p ˃ 0.05).Conclusions There could be dose-response between frequency of breaks in sedentary time and glucose. Interrupting sedentary time every 15 min could produce better glucose control

Critical success index or F measure to validate the accuracy of administrative healthcare data identifying epilepsy in deceased adults in Scotland

Background: Methods to undertake diagnostic accuracy studies of administrative epilepsy data are challenged bylack of a way to reliably rank case-ascertainment algorithms in order of their accuracy. This is because it isdifficult to know how to prioritise positive predictive value (PPV) and sensitivity (Sens). Large numbers of truenegative (TN) instances frequently found in epilepsy studies make it difficult to discriminate algorithm accuracyon the basis of negative predictive value (NPV) and specificity (Spec) as these become inflated (usually &gt;90%).This study demonstrates the complementary value of using weather forecasting or machine learning metricscritical success index (CSI) or F measure, respectively, as unitary metrics combining PPV and sensitivity. Wereanalyse data published in a diagnostic accuracy study of administrative epilepsy mortality data in Scotland.Method: CSI was calculated as 1/[(1/PPV) + (1/Sens) – 1]. F measure was calculated as 2.PPV.Sens/(PPV +Sens). CSI and F values range from 0 to 1, interpreted as 0 = inaccurate prediction and 1 = perfect accuracy. Thepublished algorithms were reanalysed using these and their accuracy re-ranked according to CSI in order to allowcomparison to the original rankings.Results: CSI scores were conservative (range 0.02–0.826), always less than or equal to the lower of the correspondingPPV (range 39–100%) and sensitivity (range 2–93%). F values were less conservative (range0.039–0.905), sometimes higher than either PPV or sensitivity, but were always higher than CSI. Low CSI and Fvalues occurred when there was a large difference between PPV and sensitivity, e.g. CSI was 0.02 and F was0.039 in an instance when PPV was 100% and sensitivity was 2%. Algorithms with both high PPV and sensitivityperformed best in terms of CSI and F measure, e.g. CSI was 0.826 and F was 0.905 in an instance when PPV was90% and sensitivity was 91%.Conclusion: CSI or F measure can combine PPV and sensitivity values into a convenient single metric that is easierto interpret and rank in terms of diagnostic accuracy than trying to rank diagnostic accuracy according to the twomeasures themselves. CSI or F prioritise instances where both PPV and sensitivity are high over instances wherethere are large differences between PPV and sensitivity (even if one of these is very high), allowing diagnosticaccuracy thresholds based on combined PPV and sensitivity to be determined. Therefore, CSI or F measures maybe helpful complementary metrics to report alongside PPV and sensitivity in diagnostic accuracy studies ofadministrative epilepsy data

Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters coul

Pacific climate reflected in Waipuna Cave drip water hydrochemistry

Cave microclimate and geochemical monitoring is vitally important for correct interpretations of proxy time series from speleothems with regard to past climatic and environmental dynamics. We present results of a comprehensive cave-monitoring programme in Waipuna Cave in the North Island of New Zealand, a region that is strongly influenced by the Southern Westerlies and the El Niño-Southern Oscillation (ENSO). This study aims to characterise the response of the Waipuna Cave hydrological system to atmospheric circulation dynamics in the southwestern Pacific region in order to assure the quality of ongoing palaeo-environmental reconstructions from this cave. Drip water from 10 drip sites was collected at roughly monthly intervals for a period of ca. 3 years for isotopic (d18O, dD, d-excess parameter, d17O, and 17Oexcess) and elemental (Mg=Ca and Sr=Ca) analysis. The monitoring included spot measurements of drip rates and cave air CO2 concentration. Cave air temperature and drip rates were also continuously recorded by automatic loggers. These datasets were compared to surface air temperature, rainfall, and potential evaporation from nearby meteorological stations to test the degree of signal transfer and expression of surface environmental conditions in Waipuna Cave hydrochemistry. Based on the drip response dynamics to rainfall and other characteristics, we identified three types of discharge associated with hydrological routing in Waipuna Cave: (i) type 1-diffuse flow, (ii) type 2-fracture flow, and (iii) type 3-combined flow. Drip water isotopes do not reflect seasonal variability but show higher values during severe drought. Drip water d18O values are characterised by small variability and reflect the mean isotopic signature of precipitation, testifying to rapid and thorough homogenisation in the epikarst. Mg=Ca and Sr=Ca ratios in drip waters are predominantly controlled by prior calcite precipitation (PCP). Prior calcite precipitation is strongest during austral summer (December-February), reflecting drier conditions and a lack of effec tive infiltration, and is weakest during the wet austral winter (July-September). The Sr=Ca ratio is particularly sensitive to ENSO conditions due to the interplay of congruent or incongruent host rock dissolution, which manifests itself in lower Sr=Ca in above-average warmer and wetter (La Niña-like) conditions. Our microclimatic observations at Waipuna Cave provide a valuable baseline for the rigorous interpretation of speleothem proxy records aiming at reconstructing the past expression of Pacific climate modes. © 2020 Author(s)

Lignin oxidation products in soil, dripwater and speleothems from four different sites in New Zealand

Lignin oxidation products (LOPs) are widely used as vegetation proxies in climate archives, such as sediment and peat cores. The total LOP concentration, Σ8, provides information on the abundance of vegetation, while the ratios C/V and S/V of the different LOP groups also provide information on the type of vegetation. Recently, LOP analysis has been successfully applied to speleothem archives. However, there are many open questions concerning the transport and microbial degradation of LOPs on their way from the soil into the cave system. These processes could potentially alter the original source-dependent LOP signals, in particular the C/V and S/V ratios, and thus complicate their interpretation in terms of past vegetation changes. We analyzed LOPs in leaf litter and different soil horizons as well as dripwater and flowstone samples from four different cave sites from different vegetation zones in New Zealand using ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry. We test whether the original source-dependent LOP signal of the overlying vegetation is preserved and can be recovered from flowstone samples and investigate how the signal is altered by the transport from the soil to the cave. The LOP concentrations range from mg g−1 in the soil to ng g−1 in the flowstones. Our results demonstrate that, from the soil to the flowstone, the C/V and S/V ratios both increase, while the total lignin content, Σ8, strongly decreases. This shows that the LOP signal is strongly influenced by both transport and degradation processes. Nevertheless, the relative LOP signal from the overlying soil at the different cave sites is preserved in the flowstone. We emphasize that for the interpretation of C/V and S/V ratios in terms of past vegetation changes, it is important to compare only samples of the same type (e.g., speleothem, dripwater or soil) and to evaluate only relative variations

The Three Rs: The Way Forward

This is the report of the eleventh of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM), which was established in 1991 by the European Commission. ECVAM\u27s main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures which would enable it to become well-informed about the state-of-the-art of non-animal test development and validation. and the potential for the possible incorporation of replacement alternative tests into regulatory procedures. It was decided that this would be best achieved by the organisation of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward

Patient-reported barriers to accepting a technological adherence package in the MAGNIFY trial.

Peer reviewedPostprin

Development of Micro-Electrode Array Based Tests for Neurotoxicity: Assessment of Interlaboratory Reproducibility with Neuroactive Chemicals

Neuronal assemblies within the nervous system produce electrical activity that can be recorded in terms of action potential patterns. Such patterns provide a sensitive endpoint to detect effects of a variety of chemical and physical perturbations. They are a function of synaptic changes and do not necessarily involve structural alterations. In vitro neuronal networks (NNs) grown on micro-electrode arrays (MEAs) respond to neuroactive substances as well as the in vivo brain. As such, they constitute a valuable tool for investigating changes in the electrophysiological activity of the neurons in response to chemical exposures. However, the reproducibility of NN responses to chemical exposure has not been systematically documented. To this purpose six independent laboratories (in Europe and in USA) evaluated the response to the same pharmacological compounds (Fluoxetine, Muscimol, and Verapamil) in primary neuronal cultures. Common standardization principles and acceptance criteria for the quality of the cultures have been established to compare the obtained results. These studies involved more than 100 experiments before the final conclusions have been drawn that MEA technology has a potential for standard in vitro neurotoxicity/neuropharmacology evaluation. The obtained results show good intra- and inter-laboratory reproducibility of the responses. The consistent inhibitory effects of the compounds were observed in all the laboratories with the 50% Inhibiting Concentrations (IC50s) ranging from: (mean ± SEM, in μM) 1.53 ± 0.17 to 5.4 ± 0.7 (n = 35) for Fluoxetine, 0.16 ± 0.03 to 0.38 ± 0.16 μM (n = 35) for Muscimol, and 2.68 ± 0.32 to 5.23 ± 1.7 (n = 32) for Verapamil. The outcome of this study indicates that the MEA approach is a robust tool leading to reproducible results. The future direction will be to extend the set of testing compounds and to propose the MEA approach as a standard screen for identification and prioritization of chemicals with neurotoxicity potential