Taurine is a potent activator of extrasynaptic GABAA receptors in the thalamus

Taurine is one of the most abundant free amino acids in the brain. In a number of studies, taurine has been reported to activate glycine receptors (Gly-Rs) at moderate concentrations (>= 100 mu M), and to be a weak agonist at GABA(A) receptors (GABA(A)-Rs), which are usually activated at high concentrations (>= 1 mM). In this study, we show that taurine reduced the excitability of thalamocortical relay neurons and activated both extrasynaptic GABAA-Rs and Gly-Rs in neurons in the mouse ventrobasal (VB) thalamus. Low concentrations of taurine (10 - 100 mu M) decreased neuronal input resistance and firing frequency, and elicited a steady outward current under voltage clamp, but had no effects on fast inhibitory synaptic currents. Currents elicited by 50 mu M taurine were abolished by gabazine, insensitive to midazolam, and partially blocked by 20 mu M Zn2+, consistent with the pharmacological properties of extrasynaptic GABA(A)-Rs (alpha 4 beta 2 delta subtype) involved in tonic inhibition in the thalamus. Tonic inhibition was enhanced by an inhibitor of taurine transport, suggesting that taurine can act as an endogenous activator of these receptors. Taurine-evoked currents were absent in relay neurons from GABA(A)-R alpha 4 subunit knock-out mice. The amplitude of the taurine current was larger in neurons from adult mice than juvenile mice. Taurine was a more potent agonist at recombinant alpha(4)beta 2 delta GABA(A)-Rs than at alpha 1 beta 2 gamma 2 GABA(A)-Rs. We conclude that physiological concentrations of taurine can inhibit VB neurons via activation of extrasynaptic GABA(A)-Rs and that taurine may function as an endogenous regulator of excitability and network activity in the thalamus

Long term cost effectiveness of interventions for obesity:A Mendelian randomisation study

Background The prevalence of obesity has increased in the United Kingdom, and reliably measuring the impact on quality of life and the total healthcare cost from obesity is key to informing the cost-effectiveness of interventions that target obesity, and determining healthcare funding. Current methods for estimating cost-effectiveness of interventions for obesity may be subject to confounding and reverse causation. The aim of this study is to apply a new approach using mendelian randomisation for estimating the cost-effectiveness of interventions that target body mass index (BMI), which may be less affected by confounding and reverse causation than previous approaches. Methods and findings We estimated health-related quality-adjusted life years (QALYs) and both primary and secondary healthcare costs for 310,913 men and women of white British ancestry aged between 39 and 72 years in UK Biobank between recruitment (2006 to 2010) and 31 March 2017. We then estimated the causal effect of differences in BMI on QALYs and total healthcare costs using mendelian randomisation. For this, we used instrumental variable regression with a polygenic risk score (PRS) for BMI, derived using a genome-wide association study (GWAS) of BMI, with age, sex, recruitment centre, and 40 genetic principal components as covariables to estimate the effect of a unit increase in BMI on QALYs and total healthcare costs. Finally, we used simulations to estimate the likely effect on BMI of policy relevant interventions for BMI, then used the mendelian randomisation estimates to estimate the cost-effectiveness of these interventions. A unit increase in BMI decreased QALYs by 0.65% of a QALY (95% confidence interval [CI]: 0.49% to 0.81%) per year and increased annual total healthcare costs by £42.23 (95% CI: £32.95 to £51.51) per person. When considering only health conditions usually considered in previous cost-effectiveness modelling studies (cancer, cardiovascular disease, cerebrovascular disease, and type 2 diabetes), we estimated that a unit increase in BMI decreased QALYs by only 0.16% of a QALY (95% CI: 0.10% to 0.22%) per year. We estimated that both laparoscopic bariatric surgery among individuals with BMI greater than 35 kg/m2, and restricting volume promotions for high fat, salt, and sugar products, would increase QALYs and decrease total healthcare costs, with net monetary benefits (at £20,000 per QALY) of £13,936 (95% CI: £8,112 to £20,658) per person over 20 years, and £546 million (95% CI: £435 million to £671 million) in total per year, respectively. The main limitations of this approach are that mendelian randomisation relies on assumptions that cannot be proven, including the absence of directional pleiotropy, and that genotypes are independent of confounders. Conclusions Mendelian randomisation can be used to estimate the impact of interventions on quality of life and healthcare costs. We observed that the effect of increasing BMI on health-related quality of life is much larger when accounting for 240 chronic health conditions, compared with only a limited selection. This means that previous cost-effectiveness studies have likely underestimated the effect of BMI on quality of life and, therefore, the potential cost-effectiveness of interventions to reduce BMI

Recent Evolution of Glaciers in the Manaslu Region of Nepal From Satellite Imagery and UAV Data (1970–2019)

Glacierized mountain ranges such as the Himalaya comprise a variety of glacier types, including clean and debris-covered glaciers. Monitoring their behaviour over time requires an assessment of changes in area and elevation along with surface features and geomorphology. In this paper we quantify the surface evolution of glacier systems in the Manaslu region of Nepal over the last five decades using 2013/2019 multi-sensor imagery and elevation data constructed from 1970 declassified Corona imagery and 1970 declassified Corona imagery. We investigate area changes, glacier thickness, geodetic glacier mass balance and surface velocity changes at regional scales and focus on the Ponkar Glacier and Thulagi Glacier and Lake for an in-depth assessment of surface geomorphology and surface feature dynamics (ponds, vegetation and ice cliffs). The time series of surface elevation changes for the lower ablation area of Ponkar Glacier is extended using 2019 UAV-based imagery and field-based ablation rates measured over the period 2016–2019. Glaciers in the Manaslu region experienced a mean area loss of −0.26 ± 0.0001% a−1 between 1970 and 2019. The mean surface lowering was −0.20 ± 0.02 ma−1 over the period 1970 to 2013, corresponding to a regional geodetic mass balance of −0.17 ± 0.03 m w. e.a−1. Overall, debris-covered glaciers had slightly higher thinning rates compared to clean ice glaciers; lake-terminating glaciers had double thinning rates compared to land-terminating glaciers. Individual glacier mass balance was negatively controlled by glacier slope and mean glacier elevation. During the period 1970 to 2013, Ponkar Glacier had a geodetic mass balance of −0.06 ± 0.01 m w. e.a−1, inversely correlated with parts of the central trunk thickening. Between 2013 and 2019 there was a nine-fold increase in the thinning rates over the lower parts of the glacier tongue relative to the period 1970–2013. Ice-surface morphology changes between 1970 and 2019 on Ponkar Glacier include a decrease in ogives and open crevasses, an increase in ice cliffs and ponds and the expansion of the supraglacial debris and ice-surface vegetation. These changes point to reduced ice-dynamic activity and are commensurate with the observed recession and negative glacier mass balance over the last five decades.publishedVersio

Recent Evolution of Glaciers in the Manaslu Region of Nepal From Satellite Imagery and UAV Data (1970–2019)

Glacierized mountain ranges such as the Himalaya comprise a variety of glacier types, including clean and debris-covered glaciers. Monitoring their behaviour over time requires an assessment of changes in area and elevation along with surface features and geomorphology. In this paper we quantify the surface evolution of glacier systems in the Manaslu region of Nepal over the last five decades using 2013/2019 multi-sensor imagery and elevation data constructed from 1970 declassified Corona imagery and 1970 declassified Corona imagery. We investigate area changes, glacier thickness, geodetic glacier mass balance and surface velocity changes at regional scales and focus on the Ponkar Glacier and Thulagi Glacier and Lake for an in-depth assessment of surface geomorphology and surface feature dynamics (ponds, vegetation and ice cliffs). The time series of surface elevation changes for the lower ablation area of Ponkar Glacier is extended using 2019 UAV-based imagery and field-based ablation rates measured over the period 2016–2019. Glaciers in the Manaslu region experienced a mean area loss of −0.26 ± 0.0001% a−1 between 1970 and 2019. The mean surface lowering was −0.20 ± 0.02 ma−1 over the period 1970 to 2013, corresponding to a regional geodetic mass balance of −0.17 ± 0.03 m w. e.a−1. Overall, debris-covered glaciers had slightly higher thinning rates compared to clean ice glaciers; lake-terminating glaciers had double thinning rates compared to land-terminating glaciers. Individual glacier mass balance was negatively controlled by glacier slope and mean glacier elevation. During the period 1970 to 2013, Ponkar Glacier had a geodetic mass balance of −0.06 ± 0.01 m w. e.a−1, inversely correlated with parts of the central trunk thickening. Between 2013 and 2019 there was a nine-fold increase in the thinning rates over the lower parts of the glacier tongue relative to the period 1970–2013. Ice-surface morphology changes between 1970 and 2019 on Ponkar Glacier include a decrease in ogives and open crevasses, an increase in ice cliffs and ponds and the expansion of the supraglacial debris and ice-surface vegetation. These changes point to reduced ice-dynamic activity and are commensurate with the observed recession and negative glacier mass balance over the last five decades.publishedVersio

Educational attainment as a modifier for the effect of polygenic scores for cardiovascular risk factors:cross-sectional and prospective analysis of UK Biobank

BACKGROUND: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases. RESULTS: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk

Recalculation of dose for each fraction of treatment on TomoTherapy.

OBJECTIVE: The VoxTox study, linking delivered dose to toxicity requires recalculation of typically 20-37 fractions per patient, for nearly 2000 patients. This requires a non-interactive interface permitting batch calculation with multiple computers. METHODS: Data are extracted from the TomoTherapy(®) archive and processed using the computational task-management system GANGA. Doses are calculated for each fraction of radiotherapy using the daily megavoltage (MV) CT images. The calculated dose cube is saved as a digital imaging and communications in medicine RTDOSE object, which can then be read by utilities that calculate dose-volume histograms or dose surface maps. The rectum is delineated on daily MV images using an implementation of the Chan-Vese algorithm. RESULTS: On a cluster of up to 117 central processing units, dose cubes for all fractions of 151 patients took 12 days to calculate. Outlining the rectum on all slices and fractions on 151 patients took 7 h. We also present results of the Hounsfield unit (HU) calibration of TomoTherapy MV images, measured over an 8-year period, showing that the HU calibration has become less variable over time, with no large changes observed after 2011. CONCLUSION: We have developed a system for automatic dose recalculation of TomoTherapy dose distributions. This does not tie up the clinically needed planning system but can be run on a cluster of independent machines, enabling recalculation of delivered dose without user intervention. ADVANCES IN KNOWLEDGE: The use of a task management system for automation of dose calculation and outlining enables work to be scaled up to the level required for large studies.JES is supported by Cancer Research UK through the Cambridge Cancer Centre. MR, AB and KH are supported by Cancer Research UK through the VoxTox Research Programme. NGB is supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from British Institute of Radiology via http://dx.doi.org/10.1259/bjr.2015077

On the annual variability of Antarctic aerosol size distributions at Halley Research Station

The Southern Ocean and Antarctic region currently best represent one of the few places left on our planet with conditions similar to the preindustrial age. Currently, climate models have a low ability to simulate conditions forming the aerosol baseline; a major uncertainty comes from the lack of understanding of aerosol size distributions and their dynamics. Contrasting studies stress that primary sea salt aerosol can contribute significantly to the aerosol population, challenging the concept of climate biogenic regulation by new particle formation (NPF) from dimethyl sulfide marine emissions. We present a statistical cluster analysis of the physical characteristics of particle size distributions (PSDs) collected at Halley (Antarctica) for the year 2015 (89 % data coverage; 6-209 nm size range; daily size resolution). By applying the Hartigan-Wong k-mean method we find eight clusters describing the entire aerosol population. Three clusters show pristine average low particle number concentrations (<121-179 cm(-3)) with three main modes (30, 75-95 and 135-160 nm) and represent 57 % of the annual PSD (up to 89 %-100 % during winter and 34 %-65 % during summer based on monthly averages). Nucleation and Aitken mode PSD clusters dominate summer months (SeptemberJanuary, 59 %-90 %), whereas a clear bimodal distribution (43 and 134 nm, respectively; Hoppel minimum at mode 75 nm) is seen only during the December-April period (6%-21 %). Major findings of the current work include: (1) NPF and growth events originate from both the sea ice marginal zone and the Antarctic plateau, strongly suggesting multiple vertical origins, including the marine boundary layer and free troposphere; (2) very low particle number concentrations are detected for a substantial part of the year (57 %), including summer (34 %-65 %), suggesting that the strong annual aerosol concentration cycle is driven by a short temporal interval of strong NPF events; (3) a unique pristine aerosol cluster is seen with a bimodal size distribution (75 and 160 nm, respectively), strongly associated with high wind speed and possibly associated with blowing snow and sea spray sea salt, dominating the winter aerosol population (34 %-54 %). A brief comparison with two other stations (Dome C - Concordia- and King Sejong Station) during the year 2015 (240 d overlap) shows that the dynamics of aerosol number concentrations and distributions are more complex than the simple sulfate-sea-spray binary combination, and it is likely that an array of additional chemical components and processes drive the aerosol population. A conceptual illustration is proposed indicating the various atmospheric processes related to the Antarctic aerosols, with particular emphasis on the origin of new particle formation and growth.Peer reviewe