Enviro-HIRLAM online integrated meteorology-chemistry modelling system: strategy, methodology, developments and applications (v7.2)

This is the final version. Available on open access from the European Geosciences Union via the DOI in this recordCode and data availability. The Enviro-HIRLAM modelling system is a community model. The source code is available for non-commercial use (i.e. research, development and science education) upon agreement through contact with Bent Hansen Sass ([email protected]) and Roman Nuterman ([email protected]). Documentation, educational materials and practical exercises are available from http://hirlam.org and http://hirlam.org/index.php/ documentation/chemistry-branch, and YSSS training schools (http: //netfam.fmi.fi/YSSS08, http://www.ysss.osenu.org.ua and http:// aveirosummerschool2014.web.ua.pt).The Environment – High Resolution Limited Area Model (Enviro-HIRLAM) is developed as a fully online integrated numerical weather prediction (NWP) and atmospheric chemical transport (ACT) model for research and forecasting of joint meteorological, chemical and biological weather. The integrated modelling system is developed by the Danish Meteorological Institute (DMI) in collaboration with several European universities. It is the baseline system in the HIRLAM Chemical Branch and used in several countries and different applications. The development was initiated at DMI more than 15 years ago. The model is based on the HIRLAM NWP model with online integrated pollutant transport and dispersion, chemistry, aerosol dynamics, deposition and atmospheric composition feedbacks. To make the model suitable for chemical weather forecasting in urban areas, the meteorological part was improved by implementation of urban parameterisations. The dynamical core was improved by implementing a locally mass-conserving semi-Lagrangian numerical advection scheme, which improves forecast accuracy and model performance. The current version (7.2), in comparison with previous versions, has a more advanced and cost-efficient chemistry, aerosol multi-compound approach, aerosol feedbacks (direct and semi-direct) on radiation and (first and second indirect effects) on cloud microphysics. Since 2004, the Enviro-HIRLAM has been used for different studies, including operational pollen forecasting for Denmark since 2009 and operational forecasting atmospheric composition with downscaling for China since 2017. Following the main research and development strategy, further model developments will be extended towards the new NWP platform – HARMONIE. Different aspects of online coupling methodology, research strategy and possible applications of the modelling system, and fit-for-purpose model configurations for the meteorological and air quality communities are discussed

Three dimensional three component whole heart cardiovascular magnetic resonance velocity mapping: comparison of flow measurements from 3D and 2D acquisitions

<p>Abstract</p> <p>Background</p> <p>Two-dimensional, unidirectionally encoded, cardiovascular magnetic resonance (CMR) velocity mapping is an established technique for the quantification of blood flow in large vessels. However, it requires an operator to correctly align the planes of acquisition. If all three directional components of velocity are measured for each voxel of a 3D volume through the phases of the cardiac cycle, blood flow through any chosen plane can potentially be calculated retrospectively. The initial acquisition is then more time consuming but relatively operator independent.</p> <p>Aims</p> <p>To compare the curves and volumes of flow derived from conventional 2D and comprehensive 3D flow acquisitions in a steady state flow model, and in vivo through planes transecting the ascending aorta and pulmonary trunk in 10 healthy volunteers.</p> <p>Methods</p> <p>Using a 1.5 T Phillips Intera CMR system, 3D acquisitions used an anisotropic 3D segmented k-space phase contrast gradient echo sequence with a short EPI readout, with prospective ECG and diaphragm navigator gating. The 2D acquisitions used segmented k-space phase contrast with prospective ECG and diaphragm navigator gating. Quantitative flow analyses were performed retrospectively with dedicated software for both the in vivo and in vitro acquisitions.</p> <p>Results</p> <p>Analysis of in vitro data found the 3D technique to have overestimated the continuous flow rate by approximately 5% across the entire applied flow range. In vivo, the 2D and the 3D techniques yielded similar volumetric flow curves and measurements. Aortic flow: (mean ± SD), 2D = 89.5 ± 13.5 ml & 3D = 92.7 ± 17.5 ml. Pulmonary flow: 2D = 98.8 ± 18.4 ml & 3D = 94.9 ± 19.0 ml). Each in vivo 3D acquisition took about 8 minutes or more.</p> <p>Conclusion</p> <p>Flow measurements derived from the 3D and 2D acquisitions were comparable. Although time consuming, comprehensive 3D velocity acquisition could be relatively operator independent, and could potentially yield information on flow through several retrospectively chosen planes, for example in patients with congenital or valvular heart disease.</p

Image quality and diagnostic accuracy of unenhanced SSFP MR angiography compared with conventional contrast-enhanced MR angiography for the assessment of thoracic aortic diseases

The purpose of this study was to determine the image quality and diagnostic accuracy of three-dimensional (3D) unenhanced steady state free precession (SSFP) magnetic resonance angiography (MRA) for the evaluation of thoracic aortic diseases. Fifty consecutive patients with known or suspected thoracic aortic disease underwent free-breathing ECG-gated unenhanced SSFP MRA with non-selective radiofrequency excitation and contrast-enhanced (CE) MRA of the thorax at 1.5 T. Two readers independently evaluated the two datasets for image quality in the aortic root, ascending aorta, aortic arch, descending aorta, and origins of supra-aortic arteries, and for abnormal findings. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were determined for both datasets. Sensitivity, specificity, and diagnostic accuracy of unenhanced SSFP MRA for the diagnosis of aortic abnormalities were determined. Abnormal aortic findings, including aneurysm (n = 47), coarctation (n = 14), dissection (n = 12), aortic graft (n = 6), intramural hematoma (n = 11), mural thrombus in the aortic arch (n = 1), and penetrating aortic ulcer (n = 9), were confidently detected on both datasets. Sensitivity, specificity, and diagnostic accuracy of SSFP MRA for the detection of aortic disease were 100% with CE-MRA serving as a reference standard. Image quality of the aortic root was significantly higher on SSFP MRA (P &lt; 0.001) with no significant difference for other aortic segments (P &gt; 0.05). SNR and CNR values were higher for all segments on SSFP MRA (P &lt; 0.01). Our results suggest that free-breathing navigator-gated 3D SSFP MRA with non-selective radiofrequency excitation is a promising technique that provides high image quality and diagnostic accuracy for the assessment of thoracic aortic disease without the need for intravenous contrast material

Alternative statistical methods for estimating efficacy of interferon beta-1b for multiple sclerosis clinical trials

<p>Abstract</p> <p>Background</p> <p>In the randomized study of interferon beta-1b (IFN beta-1b) for multiple sclerosis (MS), it has usually been evaluated the simple annual relapse rate as the study endpoint. This study aimed to investigate the performance of various regression models using information regarding the time to each recurrent event and considering the MS specific data generation process, and to estimate the treatment effect of a MS clinical trial data.</p> <p>Methods</p> <p>We conducted a simulation study with consideration of the pathological characteristics of MS, and applied alternative efficacy estimation methods to real clinical trial data, including 5 extended Cox regression models for time-to-event analysis, a Poisson regression model and a Poisson regression model with Generalized Estimating Equations (GEE). We adjusted for other important covariates that may have affected the outcome.</p> <p>Results</p> <p>We compared the simulation results for each model. The hazard ratios of real data were estimated for each model including the effects of other covariates. The results (hazard ratios of high-dose to low-dose) of all models were approximately 0.7 (range, 0.613 - 0.769), whereas the annual relapse rate ratio was 0.714.</p> <p>Conclusions</p> <p>The precision of the treatment estimation was increased by application of the alternative models. This suggests that the use of alternative models that include recurrence event data may provide better analyses.</p

Post traumatic brain perfusion SPECT analysis using reconstructed ROI maps of radioactive microsphere derived cerebral blood flow and statistical parametric mapping

<p>Abstract</p> <p>Background</p> <p>Assessment of cerebral blood flow (CBF) by SPECT could be important in the management of patients with severe traumatic brain injury (TBI) because changes in regional CBF can affect outcome by promoting edema formation and intracranial pressure elevation (with cerebral hyperemia), or by causing secondary ischemic injury including post-traumatic stroke. The purpose of this study was to establish an improved method for evaluating regional CBF changes after TBI in piglets.</p> <p>Methods</p> <p>The focal effects of moderate traumatic brain injury (TBI) on cerebral blood flow (CBF) by SPECT cerebral blood perfusion (CBP) imaging in an animal model were investigated by parallelized statistical techniques. Regional CBF was measured by radioactive microspheres and by SPECT 2 hours after injury in sham-operated piglets versus those receiving severe TBI by fluid-percussion injury to the left parietal lobe. Qualitative SPECT CBP accuracy was assessed against reference radioactive microsphere regional CBF measurements by map reconstruction, registration and smoothing. Cerebral hypoperfusion in the test group was identified at the voxel level using statistical parametric mapping (SPM).</p> <p>Results</p> <p>A significant area of hypoperfusion (P < 0.01) was found as a response to the TBI. Statistical mapping of the reference microsphere CBF data confirms a focal decrease found with SPECT and SPM.</p> <p>Conclusion</p> <p>The suitability of SPM for application to the experimental model and ability to provide insight into CBF changes in response to traumatic injury was validated by the SPECT SPM result of a decrease in CBP at the left parietal region injury area of the test group. Further study and correlation of this characteristic lesion with long-term outcomes and auxiliary diagnostic modalities is critical to developing more effective critical care treatment guidelines and automated medical imaging processing techniques.</p

Serotype-specific mortality from invasive Streptococcus pneumoniae disease revisited

BACKGROUND: Invasive infection with Streptococcus pneumoniae (pneumococci) causes significant morbidity and mortality. Case series and experimental data have shown that the capsular serotype is involved in the pathogenesis and a determinant of disease outcome. METHODS: Retrospective review of 464 cases of invasive disease among adults diagnosed between 1990 and 2001. Multivariate Cox proportional hazard analysis. RESULTS: After adjustment for other markers of disease severity, we found that infection with serotype 3 was associated with an increased relative risk (RR) of death of 2.54 (95% confidence interval (CI): 1.22–5.27), whereas infection with serotype 1 was associated with a decreased risk of death (RR 0.23 (95% CI, 0.06–0.97)). Additionally, older age, relative leucopenia and relative hypothermia were independent predictors of mortality. CONCLUSION: Our study shows that capsular serotypes independently influenced the outcome from invasive pneumococcal disease. The limitations of the current polysaccharide pneumococcal vaccine warrant the development of alternative vaccines. We suggest that the virulence of pneumococcal serotypes should be considered in the design of novel vaccines

Neutrophils Reduce the Parasite Burden in Leishmania (Leishmania) amazonensis-Infected Macrophages

Background: Studies on the role of neutrophils in Leishmania infection were mainly performed with L. (L) major, whereas less information is available for L. (L) amazonensis. Previous results from our laboratory showed a large infiltrate of neutrophils in the site of infection in a mouse strain resistant to L. (L.) amazonensis (C3H/HePas). in contrast, the susceptible strain (BALB/c) displayed a predominance of macrophages harboring a high number of amastigotes and very few neutrophils. These findings led us to investigate the interaction of inflammatory neutrophils with L. (L.) amazonensis-infected macrophages in vitro.Methodology/Principal Findings: Mouse peritoneal macrophages infected with L. (L.) amazonensis were co-cultured with inflammatory neutrophils, and after four days, the infection was quantified microscopically. Data are representative of three experiments with similar results. the main findings were 1) intracellular parasites were efficiently destroyed in the co-cultures; 2) the leishmanicidal effect was similar when cells were obtained from mouse strains resistant (C3H/HePas) or susceptible (BALB/c) to L. (L.) amazonensis; 3) parasite destruction did not require contact between infected macrophages and neutrophils; 4) tumor necrosis factor alpha (TNF-alpha), neutrophil elastase and platelet activating factor (PAF) were involved with the leishmanicidal activity, and 5) destruction of the parasites did not depend on generation of oxygen or nitrogen radicals, indicating that parasite clearance did not involve the classical pathway of macrophage activation by TNF-alpha, as reported for other Leishmania species.Conclusions/Significance: the present results provide evidence that neutrophils in concert with macrophages play a previously unrecognized leishmanicidal effect on L. (L.) amazonensis. We believe these findings may help to understand the mechanisms involved in innate immunity in cutaneous infection by this Leishmania species.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilWeb of Scienc

Accelerated CMR using zonal, parallel and prior knowledge driven imaging methods

Accelerated imaging is highly relevant for many CMR applications as competing constraints with respect to spatiotemporal resolution and tolerable scan times are frequently posed. Three approaches, all involving data undersampling to increase scan efficiencies, are discussed in this review. Zonal imaging can be considered a niche but nevertheless has found application in coronary imaging and CMR flow measurements. Current work on parallel-transmit systems is expected to revive the interest in zonal imaging techniques. The second and main approach to speeding up CMR sequences has been parallel imaging. A wide range of CMR applications has benefited from parallel imaging with reduction factors of two to three routinely applied for functional assessment, perfusion, viability and coronary imaging. Large coil arrays, as are becoming increasingly available, are expected to support reduction factors greater than three to four in particular in combination with 3D imaging protocols. Despite these prospects, theoretical work has indicated fundamental limits of coil encoding at clinically available magnetic field strengths. In that respect, alternative approaches exploiting prior knowledge about the object being imaged as such or jointly with parallel imaging have attracted considerable attention. Five to eight-fold scan accelerations in cine and dynamic CMR applications have been reported and image quality has been found to be favorable relative to using parallel imaging alone

Back pain outcomes in primary care following a practice improvement intervention:- a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Back pain is one of the UK's costliest and least understood health problems, whose prevalence still seems to be increasing. Educational interventions for general practitioners on back pain appear to have had little impact on practice, but these did not include quality improvement learning, involve patients in the learning, record costs or document practice activities as well as patient outcomes.</p> <p>Methods</p> <p>We assessed the outcome of providing information about quality improvement techniques and evidence-based practice for back pain using the Clinical Value Compass. This included clinical outcomes (Roland and Morris Disability Questionnaire), functional outcomes, costs of care and patient satisfaction. We provided workshops which used an action learning approach and collected before and after data on routine practice activity from practice electronic databases. In parallel, we studied outcomes in a separate cohort of patients with acute and sub-acute non-specific back pain recruited from the same practices over the same time period. Patient data were analysed as a prospective, split-cohort study with assessments at baseline and eight weeks following the first consultation.</p> <p>Results</p> <p>Data for 1014 patients were recorded in the practice database study, and 101 patients in the prospective cohort study. We found that practice activities, costs and patient outcomes changed little after the intervention. However, the intervention was associated with a small, but statistically significant reduction in disability in female patients. Additionally, baseline disability, downheartedness, self-rated health and leg pain had small but statistically significant effects (p < 0.05) on follow-up disability scores in some subgroups.</p> <p>Conclusions</p> <p>GP education for back pain that both includes health improvement methodologies and involves patients may yield additional benefits for some patients without large changes in patterns of practice activity. The effects in this study were small and limited and the reasons for them remain obscure. However, such is the impact of back pain and its frequency of consultation in general practice that this kind of improvement methodology deserves further consideration.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN30420389">ISRCTN30420389</a></p

Covalent Protein Modification with ISG15 via a Conserved Cysteine in the Hinge Region

The ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) is strongly induced by type I interferons and displays antiviral activity. As other ubiquitin-like proteins (Ubls), ISG15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the C-terminal glycine of ISG15 and the side chains of lysine residues in the substrates (ISGylation). ISG15 consists of two ubiquitin-like domains that are separated by a hinge region. In many orthologs, this region contains a single highly reactive cysteine residue. Several hundred potential substrates for ISGylation have been identified but only a few of them have been rigorously verified. In order to investigate the modification of several ISG15 substrates, we have purified ISG15 conjugates from cell extracts by metal-chelate affinity purification and immunoprecipitations. We found that the levels of proteins modified by human ISG15 can be decreased by the addition of reducing agents. With the help of thiol blocking reagents, a mutational analysis and miRNA mediated knock-down of ISG15 expression, we revealed that this modification occurs in living cells via a disulphide bridge between the substrates and Cys78 in the hinge region of ISG15. While the ISG15 activating enzyme UBE1L is conjugated by ISG15 in the classical way, we show that the ubiquitin conjugating enzyme Ubc13 can either be classically conjugated by ISG15 or can form a disulphide bridge with ISG15 at the active site cysteine 87. The latter modification would interfere with its function as ubiquitin conjugating enzyme. However, we found no evidence for an ISG15 modification of the dynamin-like GTPases MxA and hGBP1. These findings indicate that the analysis of potential substrates for ISG15 conjugation must be performed with great care to distinguish between the two types of modification since many assays such as immunoprecipitation or metal-chelate affinity purification are performed with little or no reducing agent present