Three weeks of interrupting sitting lowers fasting glucose and glycemic variability, but not glucose tolerance, in free-living women and men with obesity

Funding This work was supported by grants from the Novo Nordisk Foundation (NNF14OC0011493, NNF14OC0009941, NNF18CC0034900), Swedish Diabetes Foundation (DIA2018-357), Diabetes Wellness Sverige (1849-PG), Swedish Research Council (2015-00165, 2018-02389), the Strategic Research Programme in Diabetes at Karolinska Institutet (2009-1068), the Knut and Alice Wallenberg Foundation (2018-0094), and the Stockholm County Council (SLL20170159). D.D. is supported by the National Health and Medical Research Council and the Victorian Government’s OIS scheme. Acknowledgements We thank the Swedish Metabolomics Centre (Umeå University) for assisting with the lipidomic analysis and Mariam Nordstrand for efforts in the recruitment and screening of participants, and in muscle biopsy procedure. The current addresses for S.P. and B.M.G. are the School of Life Sciences, University of Nottingham, Nottingham, UK, and The Rowett Institute, University of Aberdeen, Aberdeen, UK, respectively.Peer reviewedPostprin

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs.

METHODOLOGY/PRINCIPAL FINDINGS: The experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS. CONCLUSIONS/SIGNIFICANCE: IM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs

International Veterinary Epilepsy Task Force Consensus Proposal: Diagnostic approach to epilepsy in dogs

This article outlines the consensus proposal on diagnosis of epilepsy in dogs by the International Veterinary Epilepsy Task Force. The aim of this consensus proposal is to improve consistency in the diagnosis of epilepsy in the clinical and research settings. The diagnostic approach to the patient presenting with a history of suspected epileptic seizures incorporates two fundamental steps: to establish if the events the animal is demonstrating truly represent epileptic seizures and if so, to identify their underlying cause. Differentiation of epileptic seizures from other non-epileptic episodic paroxysmal events can be challenging. Criteria that can be used to make this differentiation are presented in detail and discussed. Criteria for the diagnosis of idiopathic epilepsy (IE) are described in a three-tier system. Tier I confidence level for the diagnosis of IE is based on a history of two or more unprovoked epileptic seizures occurring at least 24 h apart, age at epileptic seizure onset of between six months and six years, unremarkable inter-ictal physical and neurological examination, and no significant abnormalities on minimum data base blood tests and urinalysis. Tier II confidence level for the diagnosis of IE is based on the factors listed in tier I and unremarkable fasting and post-prandial bile acids, magnetic resonance imaging (MRI) of the brain (based on an epilepsy-specific brain MRI protocol) and cerebrospinal fluid (CSF) analysis. Tier III confidence level for the diagnosis of IE is based on the factors listed in tier I and II and identification of electroencephalographic abnormalities characteristic for seizure disorders. The authors recommend performing MRI of the brain and routine CSF analysis, after exclusion of reactive seizures, in dogs with age at epileptic seizure onset 6 years, inter-ictal neurological abnormalities consistent with intracranial neurolocalisation, status epilepticus or cluster seizure at epileptic seizure onset, or a previous presumptive diagnosis of IE and drug-resistance with a single antiepileptic drug titrated to the highest tolerable dose

Evaluation of wetland CH4 in the Joint UK Land Environment Simulator (JULES) land surface model using satellite observations

Wetlands are the largest natural source of methane. The ability to model the emissions of methane from natural wetlands accurately is critical to our understanding of the global methane budget and how it may change under future climate scenarios. The simulation of wetland methane emissions involves a complicated system of meteorological drivers coupled to hydrological and biogeochemical processes. The Joint UK Land Environment Simulator (JULES) is a process-based land surface model that underpins the UK Earth System Model (UKESM) and is capable of generating estimates of wetland methane emissions. In this study, we use GOSAT satellite observations of atmospheric methane along with the TOMCAT global 3-D chemistry transport model to evaluate the performance of JULES in reproducing the seasonal cycle of methane over a wide range of tropical wetlands. By using an ensemble of JULES simulations with differing input data and process configurations, we investigate the relative importance of the meteorological driving data, the vegetation, the temperature dependency of wetland methane production and the wetland extent. We find that JULES typically performs well in replicating the observed methane seasonal cycle. We calculate correlation coefficients to the observed seasonal cycle of between 0.58 and 0.88 for most regions; however, the seasonal cycle amplitude is typically underestimated (by between 1.8 and 19.5 ppb). This level of performance is comparable to that typically provided by state-of-the-art data-driven wetland CH4 emission inventories. The meteorological driving data are found to be the most significant factor in determining the ensemble performance, with temperature dependency and vegetation having moderate effects. We find that neither wetland extent configuration outperforms the other, but this does lead to poor performance in some regions. We focus in detail on three African wetland regions (Sudd, Southern Africa and Congo) where we find the performance of JULES to be poor and explore the reasons for this in detail. We find that neither wetland extent configuration used is sufficient in representing the wetland distribution in these regions (underestimating the wetland seasonal cycle amplitude by 11.1, 19.5 and 10.1 ppb respectively, with correlation coefficients of 0.23, 0.01 and 0.31). We employ the Catchment-based Macro-scale Floodplain (CaMa-Flood) model to explicitly represent river and floodplain water dynamics and find that these JULES-CaMa-Flood simulations are capable of providing a wetland extent that is more consistent with observations in this regions, highlighting this as an important area for future model development.</p

Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model

BACKGROUND: Efforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic development process. One of the major factors believed to be limiting effective screening of these treatments is the absence of an animal model more predictive of human responses to treatments. The pig may potentially fill this gap with a gyrencephalic brain that is larger in size with a more similar gray-white matter composition to humans than traditional stroke animal models. In this study we develop and characterize a novel pig middle cerebral artery occlusion (MCAO) ischemic stroke model. METHODS: Eleven male pigs underwent MCAO surgery with the first 4 landrace pigs utilized to optimize stroke procedure and 7 additional Yucatan stroked pigs studied over a 90 day period. MRI analysis was done at 24 hrs and 90 days and included T2w, T2w FLAIR, T1w FLAIR and DWI sequences and associated ADC maps. Pigs were sacrificed at 90 days and underwent gross and microscopic histological evaluation. Significance in quantitative changes was determined by two-way analysis of variance and post-hoc Tukey’s Pair-Wise comparisons. RESULTS: MRI analysis of animals that underwent MCAO surgery at 24 hrs had hyperintense regions in T2w and DWI images with corresponding ADC maps having hypointense regions indicating cytotoxic edema consistent with an ischemic stroke. At 90 days, region of interest analysis of T1 FLAIR and ADC maps had an average lesion size of 59.17 cc, a loss of 8% brain matter. Histological examination of pig brains showed atrophy and loss of tissue, consistent with MRI, as well as glial scar formation and macrophage infiltration. CONCLUSIONS: The MCAO procedure led to significant and consistent strokes with high survivability. These results suggest that the pig model is potentially a robust system for the study of stroke pathophysiology and potential diagnostics and therapeutics

Quantifying the UK's carbon dioxide flux: An atmospheric inverse modelling approach using a regional measurement network

We present a method to derive atmosphericobservation-based estimates of carbon dioxide (CO 2 ) fluxes at the national scale, demonstrated using data from a network of surface tall-tower sites across the UK and Ireland over the period 2013-2014. The inversion is carried out using simulations from a Lagrangian chemical transport model and an innovative hierarchical Bayesian Markov chain Monte Carlo (MCMC) framework, which addresses some of the traditional problems faced by inverse modelling studies, such as subjectivity in the specification of model and prior uncertainties. Biospheric fluxes related to gross primary productivity and terrestrial ecosystem respiration are solved separately in the inversion and then combined a posteriori to determine net ecosystem exchange of CO 2 . Two different models, Data Assimilation Linked Ecosystem Carbon (DALEC) and Joint UK Land Environment Simulator (JULES), provide prior estimates for these fluxes. We carry out separate inversions to assess the impact of these different priors on the posterior flux estimates and evaluate the differences between the prior and posterior estimates in terms of missing model components. The Numerical Atmospheric dispersion Modelling Environment (NAME) is used to relate fluxes to the measurements taken across the regional network. Posterior CO2 estimates from the two inversions agree within estimated uncertainties, despite large differences in the prior fluxes from the different models. With our method, averaging results from 2013 and 2014, we find a total annual net biospheric flux for the UK of 8±79 TgCO 2 yr -1 (DALEC prior) and 64±85 TgCO 2 yr -1 (JULES prior), where negative values represent an uptake of CO 2 . These biospheric CO 2 estimates show that annual UK biospheric sources and sinks are roughly in balance. These annual mean estimates consistently indicate a greater net release of CO 2 than the prior estimates, which show much more pronounced uptake in summer months

Global Burden of Sickle Cell Anaemia in Children under Five, 2010-2050: Modelling Based on Demographics, Excess Mortality, and Interventions

The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400-398,800) in 2010 to 404,200 (CI: 242,500-657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900-106,100]; 2050: 140,800 [CI: 95,500-200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600-48,800]; 2050: 44,700 [CI: 27,100-70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700-59,100]; 2050: 33,900 [CI: 15,900-64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800-6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800-14,232,700) newborns with SCA globally, 85% (CI: 81%-88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed