Background
The role of selenium (Se) in the management of type 2 diabetes mellitus (T2DM) remains unclear. We systematically assessed the effectiveness and safety of Se supplementation in adults with ...T2DM.
Methods
MEDLINE, EMBASE and the Cochrane Library were searched up to April 2018 for randomised controlled trials (RCTs) evaluating the effectiveness of Se against a comparator on DM‐related outcomes.
Results
Four RCTs (241 participants) were included. In individual RCTs, Se supplementation significantly reduced fasting insulin levels mean difference (MD) = −3.6 μIU mL−1; 95% confidence interval (CI) = −6.36 to −0.84; MD = −5.8 μIU mL−1; 95% CI = −9.23 to −2.37, homeostasis model of assessment‐estimated insulin resistance (HOMA‐IR) (MD = −1; 95% CI = −1.79 to −0.21; MD = −1.6; 95% CI, −2.58 to −0.62) and homeostasis model of assessment‐estimated B cell function (HOMA‐B) (MD = −13.6; 95% CI = −23.4 to −3.8; MD = −22.6; 95% CI = −36.39 to −8.81). No effects of Se were noted on most of the other outcomes of interest. None of the RCTs assessed the mortality, diabetes‐related complications, non‐high‐density lipoprotein (non‐HDL), blood pressure and health‐related quality of life. The impact on HDL and fasting plasma glucose (FPG) was ambiguous. Only one adverse event (nausea) was reported as a reason for discontinuing the intervention; however, among the studies, the reporting was not accurate. Furthermore, only one RCT reported increase in FPG level in the Se group (MD = 36.38 mg dL−1; 95% CI = 15.39–57.37).
Conclusions
Currently, there is no evidence to support the effectiveness of Se supplementation in the T2DM population.
The performance of a new historical reanalysis, the NOAA–CIRES–DOE Twentieth Century Reanalysis version 3 (20CRv3), is evaluated via comparisons with other reanalyses and independent observations. ...This dataset provides global, 3-hourly estimates of the atmosphere from 1806 to 2015 by assimilating only surface pressure observations and prescribing sea surface temperature, sea ice concentration, and radiative forcings. Comparisons with independent observations, other reanalyses, and satellite products suggest that 20CRv3 can reliably produce atmospheric estimates on scales ranging from weather events to long-term climatic trends. Not only does 20CRv3 recreate a ‘‘best estimate’’ of the weather, including extreme events, it also provides an estimate of its confidence through the use of an ensemble. Surface pressure statistics suggest that these confidence estimates are reliable. Comparisons with independent upper-air observations in the Northern Hemisphere demonstrate that 20CRv3 has skill throughout the twentieth century. Upper-air fields from 20CRv3 in the late twentieth century and early twenty-first century correlate well with full-input reanalyses, and the correlation is predicted by the confidence fields from 20CRv3. The skill of analyzed 500-hPa geopotential heights from 20CRv3 for 1979–2015 is comparable to that of modern operational 3–4-day forecasts. Finally, 20CRv3 performs well on climate time scales. Long time series and multidecadal averages of mass, circulation, and precipitation fields agree well with modern reanalyses and station- and satellite-based products. 20CRv3 is also able to capture trends in tropospheric-layer temperatures that correlate well with independent products in the twentieth century, placing recent trends in a longer historical context.
Abstract
The ability of a compound to cause adverse effects to the liver is one of the most common reasons for drug development failures and the withdrawal of drugs from the market. Such adverse ...effects can vary tremendously in severity, leading to an array of possible drug-induced liver injuries (DILIs). As a result, it is not surprising that drug development has evolved into a complex and multifaceted process including methods aiming to identify potential liver toxicities. Unfortunately, hepatotoxicity remains one of the most complex and poorly understood areas of human toxicity; thus it is a significant challenge to identify potential hepatotoxins. The performance of existing methods to identify hepatotoxicity requires improvement. The current study details a scheme for generating chemical categories and the development of structural alerts able to identify potential hepatotoxins. The study utilized a diverse 951-compound dataset and used structural similarity methods to produce a number of structurally restricted categories. From these categories, 16 structural alerts associated with observed human hepatotoxicity were developed. Furthermore, the mechanism(s) by which these compounds cause hepatotoxicity were investigated and a mechanistic rationale was proposed, where possible, to yield mechanistically supported structural alerts. Alerts of this nature have the potential to be used in the screening of compounds to highlight potential hepatotoxicity, whilst the chemical categories themselves are important in applying read-across approaches. The scheme presented in this study also has the potential to act as a knowledge generator serving as an excellent starting platform from which to conduct additional toxicological studies.
Historical reanalyses that span more than a century are needed for a wide range of studies, from understanding large‐scale climate trends to diagnosing the impacts of individual historical extreme ...weather events. The Twentieth Century Reanalysis (20CR) Project is an effort to fill this need. It is supported by the National Oceanic and Atmospheric Administration (NOAA), the Cooperative Institute for Research in Environmental Sciences (CIRES), and the U.S. Department of Energy (DOE), and is facilitated by collaboration with the international Atmospheric Circulation Reconstructions over the Earth initiative. 20CR is the first ensemble of sub‐daily global atmospheric conditions spanning over 100 years. This provides a best estimate of the weather at any given place and time as well as an estimate of its confidence and uncertainty. While extremely useful, version 2c of this dataset (20CRv2c) has several significant issues, including inaccurate estimates of confidence and a global sea level pressure bias in the mid‐19th century. These and other issues can reduce its effectiveness for studies at many spatial and temporal scales. Therefore, the 20CR system underwent a series of developments to generate a significant new version of the reanalysis. The version 3 system (NOAA‐CIRES‐DOE 20CRv3) uses upgraded data assimilation methods including an adaptive inflation algorithm; has a newer, higher‐resolution forecast model that specifies dry air mass; and assimilates a larger set of pressure observations. These changes have improved the ensemble‐based estimates of confidence, removed spin‐up effects in the precipitation fields, and diminished the sea‐level pressure bias. Other improvements include more accurate representations of storm intensity, smaller errors, and large‐scale reductions in model bias. The 20CRv3 system is comprehensively reviewed, focusing on the aspects that have ameliorated issues in 20CRv2c. Despite the many improvements, some challenges remain, including a systematic bias in tropical precipitation and time‐varying biases in southern high‐latitude pressure fields.
A significant new version of the Twentieth Century Reanalysis data assimilation system, 20CRv3, has been developed. The 20CRv3 dataset will provide an ensemble of sub‐daily global atmospheric conditions spanning at least 180 years by assimilating only surface pressure observations into a coupled atmosphere–land forecast model. The new 20CRv3 system improves upon the previous system in several notable ways, including the use of upgraded data assimilation methods, a newer and higher‐resolution forecast model, and a larger set of available pressure observations.
Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin ...sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.
The purpose of this study was to update the existing Cancer Potency Database (CPDB) in order to support the development of a dataset of compounds, with associated points of departure (PoDs), to ...enable a review and update of currently applied values for the Threshold of Toxicological Concern (TTC) for cancer endpoints. This update of the current CPDB, last reviewed in 2012, includes the addition of new data (44 compounds and 158 studies leading to additional 359 dose-response curves). Strict inclusion criteria were established and applied to select compounds and studies with relevant cancer potency data. PoDs were calculated from dose-response modeling, including the benchmark dose (BMD) and the lower 90% confidence limits (BMDL) at a specified benchmark response (BMR) of 10%. The updated full CPDB database resulted in a total of 421 chemicals which had dose-response data that could be used to calculate PoDs. This candidate dataset for cancer TTC is provided in a transparent and adaptable format for further analysis of TTC to derive cancer potency thresholds.
EUSO-TA is a ground-based fluorescence telescope built to validate the design of ultra-high energy cosmic ray fluorescence detectors to be operated in space with the technology developed within the ...Joint Exploratory Missions for Extreme Universe Space Observatory (JEM-EUSO) program. It operates at the Telescope Array (TA) site in Utah, USA. With an external trigger provided by the Black Rock Mesa fluorescence detectors of the Telescope Array experiment, with EUSO-TA we observed air-showers from ultra-high energy cosmic rays, as well as laser events from the Central Laser Facility at the TA site and from portable lasers like the JEM-EUSO Global Light System prototype. Since the Black Rock Mesa fluorescence detectors have a ∼30 times larger field of view than EUSO-TA, they allow a primary energy reconstruction based on the observation of a large part of the shower evolution, including the shower maximum, while EUSO-TA observes only a part of it, usually far away from the maximum. To estimate the detection limits of EUSO-TA in energy and distance, a method was developed to re-scale their energy, taking into account that EUSO-TA observes only a portion of the air-showers. The method was applied on simulation sets with showers with different primaries, energy, direction, and impact point on the ground, as well as taking into account the experimental environment. EUSO-TA was simulated with an internal trigger and different elevation angles and electronics. The same method was then applied also to real measurements and compared to the simulations. In addition, the method can also be used to estimate the detection limits for experiments that are operated at high altitudes and in most cases can see the maximum of the showers. This was done for EUSO-SPB1, an instrument installed on a super-pressure balloon. Finally, the expected detection rates for EUSO-TA were also assessed using the prepared simulated event sets. The rates correspond to a few detections per recording session of 30 h of observation, depending on the background level and the configuration of the detector.
In silico
methods to predict toxicity include the use of (Quantitative) Structure-Activity Relationships ((Q)SARs) as well as grouping (category formation) allowing for read-across. A challenging ...area for in silico modelling is the prediction of chronic toxicity and the No Observed (Adverse) Effect Level (NO(A)EL) in particular. A proposed solution to the prediction of chronic toxicity is to consider organ level effects, as opposed to modelling the NO(A)EL itself. This review has focussed on the use of structural alerts to identify potential liver toxicants.
In silico
profilers, or groups of structural alerts, have been developed based on mechanisms of action and informed by current knowledge of Adverse Outcome Pathways. These profilers are robust and can be coded computationally to allow for prediction. However, they do not cover all mechanisms or modes of liver toxicity and recommendations for the improvement of these approaches are given.
Existing toxicological data may be used for a variety of purposes such as hazard and risk assessment or toxicity prediction. The potential use of such data is, in part, dependent upon their quality. ...Consideration of data quality is of key importance with respect to the application of chemicals legislation such as REACH. Whether data are being used to make regulatory decisions or build computational models, the quality of the output is reflected by the quality of the data employed. Therefore, the need to assess data quality is an important requirement for making a decision or prediction with an appropriate level of confidence. This study considers the biological and chemical factors that may impact upon toxicological data quality and discusses the assessment of data quality. Four general quality criteria are introduced and existing data quality assessment schemes are discussed. Two case study datasets of skin sensitization data are assessed for quality providing a comparison of existing assessment methods. This study also discusses the limitations and difficulties encountered during quality assessment, including the use of differing quality schemes and the global versus chemical-specific assessments of quality. Finally, a number of recommendations are made to aid future data quality assessments.
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