Chemical speciation models based upon the Pitzer activity coefficient equations, including the propagation of uncertainties. II. Tris buffers in artificial seawater at 25 °C, and an assessment of the seawater ‘Total’ pH scale

The substance Tris (or THAM, 2-amino-2-hydroxymethyl-1,3-propanediol, CAS 77–86-1), and its protonated form TrisH+, is used in the preparation of pH buffer solutions for applications in seawater chemistry. The development of an acid-base chemical speciation model of buffer solutions containing Tris, TrisH+, and the major ions of seawater is desirable so that: (i) the effects of changes in the composition of the medium on pH can be calculated; (ii) pH on the free (a measure of [H+]) and total (a measure of ([H+] + [HSO4−])) scales can be interconverted; (iii) approximations inherent in the definition of the total pH scale can be quantified; (iv) electrode pairs such as H+/Cl− and H+/Na+ can more easily be calibrated for the measurement of pH. As a first step towards these goals we have extended the Pitzer-based speciation model of Waters and Millero (Mar. Chem. 149, 8–22, 2013) for artificial seawater to include Tris and TrisH+, at 25 °C. Estimates of the variances and covariances of the additional interaction parameters were obtained by Monte Carlo simulation. This enables the total uncertainty of any model-calculated quantity (e.g., pH, speciation) to be estimated, as well as the individual contributions of all interaction parameters and equilibrium constants. This is important for model development, because it allows the key interactions to be identified. The model was tested against measured EMFs of cells containing Tris buffer in artificial seawater at 25 °C, and the mean deviation was found to be 0.13 ± 0.070 mV for salinities 20 to 40. Total variances for calculated electromotive forces of the buffer solutions are dominated by contributions from just a few interaction parameters, making it likely that the model can readily be improved. The model was used to quantify the difference between various definitions of total pH and –log10([H+] + [HSO4−]) in Tris buffer solutions at 25 °C, for the first time (item (iii) above). The results suggest that the total pH scale can readily be extended to low salinities using the established approach for substituting TrisH+ for Na+ in the buffer solutions, especially if the speciation model is used to quantify the effect on pH of the substitution. The relationships between electromotive force (EMF), and pH on the total scale, with buffer molality in artificial seawater at constant salinity are shown to be linear above about 0.01 to 0.02 mol kg−1 buffer molality. The pH of Tris buffers containing ratios of TrisH+ to Tris that vary from unity can be calculated very simply. Technical aspects of the total pH scale, such as the extrapolation of pH to zero buffer (at constant salinity), are clarified. Recommendations are made for further work to extend the model to the temperature range 0–45 °C, and improve accuracy, so that requirements (i) to (iv) above can be fully met

The association between antihypertensive treatment and serious adverse events by age and frailty: A cohort study

BACKGROUND: Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data. METHODS AND FINDINGS: This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out. CONCLUSIONS: Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment

Refocusing multiple stressor research around the targets and scales of ecological impacts

Ecological communities face a variety of environmental and anthropogenic stressors acting simultaneously. Stressor impacts can combine additively or can interact, causing synergistic or antagonistic effects. Our knowledge of when and how interactions arise is limited, as most models and experiments only consider the effect of a small number of non-interacting stressors at one or few scales of ecological organization. This is concerning because it could lead to significant underestimations or overestimations of threats to biodiversity. Furthermore, stressors have been largely classified by their source rather than by the mechanisms and ecological scales at which they act (the target). Here, we argue, first, that a more nuanced classification of stressors by target and ecological scale can generate valuable new insights and hypotheses about stressor interactions. Second, that the predictability of multiple stressor effects, and consistent patterns in their impacts, can be evaluated by examining the distribution of stressor effects across targets and ecological scales. Third, that a variety of existing mechanistic and statistical modelling tools can play an important role in our framework and advance multiple stressor research

Period and chemical evolution of SC stars

The SC and CS stars are thermal-pulsing AGB stars with C/O ratio close to unity. Within this small group, the Mira variable BH Cru recently evolved from spectral type SC (showing ZrO bands) to CS (showing weak C2). Wavelet analysis shows that the spectral evolution was accompanied by a dramatic period increase, from 420 to 540 days, indicating an expanding radius. The pulsation amplitude also increased. Old photographic plates are used to establish that the period before 1940 was around 490 days. Chemical models indicate that the spectral changes were caused by a decrease in stellar temperature, related to the increasing radius. There is no evidence for a change in C/O ratio. The evolution in BH Cru is unlikely to be related to an on-going thermal pulse. Periods of the other SC and CS stars, including nine new periods, are determined. A second SC star, LX Cyg, also shows evidence for a large increase in period, and one further star shows a period inconsistent with a previous determination. Mira periods may be intrinsically unstable for C/O ~ 1; possibly because of a feedback between the molecular opacities, pulsation amplitude, and period. LRS spectra of 6 SC stars suggest a feature at wavelength > 15 micron, which resembles one recently attributed to the iron-sulfide troilite. Chemical models predict a large abundance of FeS in SC stars, in agreement with the proposed association.Comment: 14 pages, 20 figures. MNRAS, 2004, accepted for publication. Janet Mattei, one of the authors, died on 22 March, 2004. This paper is dedicated to her memor

Predicting the risk of acute kidney injury in primary care: derivation and validation of STRATIFY-AKI

BACKGROUND: Antihypertensives reduce the risk of cardiovascular disease but are also associated with harms including acute kidney injury (AKI). Few data exist to guide clinical decision making regarding these risks. AIM: To develop a prediction model estimating the risk of AKI in people potentially indicated for antihypertensive treatment. DESIGN AND SETTING: Observational cohort study using routine primary care data from the Clinical Practice Research Datalink (CPRD) in England. METHOD: People aged ≥40 years, with at least one blood pressure measurement between 130 mmHg and 179 mmHg were included. Outcomes were admission to hospital or death with AKI within 1, 5, and 10 years. The model was derived with data from CPRD GOLD (n = 1 772 618), using a Fine-Gray competing risks approach, with subsequent recalibration using pseudo-values. External validation used data from CPRD Aurum (n = 3 805 322). RESULTS: The mean age of participants was 59.4 years and 52% were female. The final model consisted of 27 predictors and showed good discrimination at 1, 5, and 10 years (C-statistic for 10-year risk 0.821, 95% confidence interval [CI] = 0.818 to 0.823). There was some overprediction at the highest predicted probabilities (ratio of observed to expected event probability for 10-year risk 0.633, 95% CI = 0.621 to 0.645), affecting patients with the highest risk. Most patients (>95%) had a low 1- to 5-year risk of AKI, and at 10 years only 0.1% of the population had a high AKI and low CVD risk. CONCLUSION: This clinical prediction model enables GPs to accurately identify patients at high risk of AKI, which will aid treatment decisions. As the vast majority of patients were at low risk, such a model may provide useful reassurance that most antihypertensive treatment is safe and appropriate while flagging the few for whom this is not the case

EMU: Rapid prototyping of networking services

Due to their performance and flexibility, FPGAs are an attractive platform for the execution of network functions. It has been a challenge for a long time though to make FPGA programming accessible to a large audience of developers. An appealing solution is to compile code from a general-purpose language to hardware using high-level synthesis. Unfortunately, current approaches to implement rich network functionality are insufficient because they lack: (i) libraries with abstractions for common network operations and data structures, (ii) bindings to the underlying “substrate” on the FPGA, and (iii) debugging and profiling support. This paper describes Emu, a new standard library for an FPGA hardware compiler that enables developers to rapidly create and deploy network functionality. Emu allows for high-performance designs without being bound to particular packet processing paradigms. Furthermore, it supports running the same programs on CPUs, in Mininet, and on FPGAs, providing a better development environment that includes advanced debugging capabilities. We demonstrate that network functions implemented using Emu have only negligible resource and performance overheads compared with natively-written hardware versions

CODA: Accurate Detection of Functional Associations between Proteins in Eukaryotic Genomes Using Domain Fusion

Background: In order to understand how biological systems function it is necessary to determine the interactions and associations between proteins. Gene fusion prediction is one approach to detection of such functional relationships. Its use is however known to be problematic in higher eukaryotic genomes due to the presence of large homologous domain families. Here we introduce CODA (Co-Occurrence of Domains Analysis), a method to predict functional associations based on the gene fusion idiom.Methodology/Principal Findings: We apply a novel scoring scheme which takes account of the genome-specific size of homologous domain families involved in fusion to improve accuracy in predicting functional associations. We show that CODA is able to accurately predict functional similarities in human with comparison to state-of-the-art methods and show that different methods can be complementary. CODA is used to produce evidence that a currently uncharacterised human protein may be involved in pathways related to depression and that another is involved in DNA replication.Conclusions/Significance: The relative performance of different gene fusion methodologies has not previously been explored. We find that they are largely complementary, with different methods being more or less appropriate in different genomes. Our method is the only one currently available for download and can be run on an arbitrary dataset by the user. The CODA software and datasets are freely available from ftp://ftp.biochem.ucl.ac.uk/pub/gene3d_data/v6.1.0/CODA/. Predictions are also available via web services from http://funcnet.eu/