Simulating the 20 May 2013 Moore, Oklahoma tornado with a 100-metre grid-length NWP model

Since 2013, the Met Office have run a 2.2 km horizontal gridlength version of the Unified Model (MetUM) as part of the National Oceanographic and Atmospheric Administration's Hazardous Weather Testbed Spring Forecasting Experiment. In this study, we perform high resolution MetUM simulations of the 20 May 2013 Oklahoma tornado outbreak at horizontal gridlengths between 2.2 km and 100 m. Here we present results showing that at 2.2 km gridlength the MetUM is able to simulate supercell-like storms whereas at O(100 m) gridlength it is able to simulate realistic-looking supercells with tornado-like vortices. This opens up the opportunity for using such simulations to highlight areas of enhanced tornado risk ahead of time

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS. Untargeted LC-MS based metabolomics provided an in-depth profile of the macrophage metabolome, and revealed specific changes in metabolite abundance upon either individual stimuli or combined stimuli. Here, by factoring in an interaction term in the linear model, we define the metabolome interactome. This approach allowed us to determine whether stimuli interact in a synergistic or antagonistic manner. In conclusion this study demonstrates a robust approach to interrogate immune-metabolism, especially systems that model host-pathogen interactions

Bench-top characterization of an active rotor blade flap system incorporating C-block actuators

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76706/1/AIAA-1998-2108-892.pd

Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined

Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistant

Background: Protozoan Leishmania parasites are responsible for a range of clinical infections that represent a substantial challenge for global health. Amphotericin B (AmB) is increasingly used to treat Leishmania infection, so understanding the potential for resistance to this drug is an important priority. Previously we described four independently-derived AmB-resistant L. mexicana lines that exhibited resistance-associated genetic lesions resulting in altered sterol content. However, substantial phenotypic variation between these lines, including differences in virulence attributes, were not fully explained by these changes. Methods: To identify alterations in cellular metabolism potentially related to phenotypic differences between wild-type and AmB-resistant lines, we extracted metabolites and performed untargeted metabolomics by liquid chromatography-mass spectrometry. Results: We observed substantial differences in metabolite abundance between lines, arising in an apparently stochastic manner. Concerted remodeling of central carbon metabolism was not observed; however, in three lines, decreased abundance of several oligohexoses was observed. Given that the oligomannose mannogen is an important virulence factor in Leishmania, this could relate to loss of virulence in these lines. Increased abundance of the reduced forms of the oxidative stress-protective thiols trypanothione and glutathione was also observed in multiple lines. Conclusions: This dataset will provide a useful resource for understanding the molecular basis of drug resistance in Leishmania, and suggests a role for metabolic changes separate from the primary mechanism of drug resistance in determining the phenotypic profile of parasite lines subjected to experimental selection of resistance

A Participatory Action Research Study of the Collaborative Learning Process

The purpose of this participatory action research project was to identify attributes that contribute to a successful collaborative learning experience. Data analysis revealed the following emergent themes to be important: reflection and dialogue, interpersonal relationships, and group and individual responsibilities

Risk factors for dislocation after primary total hip replacement:a systematic review and meta-analysis of 125 studies involving approximately five million hip replacements

Background:&nbsp;Dislocation following total hip replacement is associated with repeated admissions to hospital and substantial costs to the health system. Factors influencing dislocation following primary total hip replacement are not well understood. We aimed to assess the association of various factors with dislocation risk following primary total hip replacement. Methods:&nbsp;We did a systematic review and meta-analysis of longitudinal studies reporting associations of patient-related, surgery-related, implant-related, and hospital-related factors with dislocation risk after primary total hip replacement. We searched MEDLINE, Embase, Web of Science, and the Cochrane Library for all relevant articles published up to March 8, 2019. Summary measures of association were calculated with relative risks (RRs) and 95% CIs. This study is registered on PROSPERO, number CRD42019121378. Findings:&nbsp;We identified 149 articles based on 125 unique studies with data on 4 633 935 primary total hip replacements and 35 264 dislocations. The incidence of dislocation ranged from 0&middot;12% to 16&middot;13%, with an overall pooled incidence of 2&middot;10% (95% CI 1&middot;83&ndash;2&middot;38) over a weighted mean follow-up duration of 6 years. Based on the median year of data collection, a significant decline in dislocation rates was observed from 1971 to 2015. The risk of dislocation did not differ significantly between male versus female patients (RR 0&middot;97; 95% CI 0&middot;88&ndash;1&middot;08), was higher in those aged 70 years and older than in those younger than 70 years (1&middot;27; 1&middot;02&ndash;1&middot;57), and was lower in those from high versus low income groups (0&middot;79; 0&middot;74&ndash;0&middot;85). White ethnicity (only when compared with Asian ethnicity), drug use disorder, and social deprivation were significantly associated with increased dislocation risk. The risk of dislocation was higher in patients with body-mass index (BMI) of 30 kg/m2&nbsp;or higher than in those with BMI lower than 30 kg/m2&nbsp;(RR 1&middot;38; 95% CI 1&middot;03&ndash;1&middot;85). Medical factors and those related to surgical history that were significantly associated with increased dislocation risk included neurological disorder, psychiatric disease, comorbidity indices, previous surgery including spinal fusion, and surgical indications including avascular necrosis, rheumatoid arthritis, inflammatory arthritis, and osteonecrosis. Surgical factors such as the anterolateral, direct anterior, or lateral approach, and posterior approach with short external rotator and capsule repair were significantly associated with reduced dislocation risk. At the implant level, larger femoral head diameters, elevated acetabular liners, dual mobility cups, cemented fixations, and standard femoral neck lengths significantly reduced the risk of dislocation. Hospital-related factors such as experienced surgeons and high surgeon procedure volume significantly reduced the risk of dislocation. Interpretation:&nbsp;Dislocation following primary total hip replacement has declined over time. Surgical approaches that reduce dislocation risk can be used by clinicians during primary total hip replacement, and alternative bearings such as dual mobility can be used in individuals at high risk of dislocation. Modifiable risk factors such as high BMI and comorbidities might also be amenable to optimisation before surgery. </div

Understanding pregnancy planning in a low-income country setting: validation of the London measure of unplanned pregnancy in Malawi

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The London Measure of Unplanned Pregnancy (LMUP) is a new and psychometrically valid measure of pregnancy intention that was developed in the United Kingdom. An improved understanding of pregnancy intention in low-income countries, where unintended pregnancies are common and maternal and neonatal deaths are high, is necessary to inform policies to address the unmet need for family planning. To this end this research aimed to validate the LMUP for use in the Chichewa language in Malawi.Methods: Three Chichewa speakers translated the LMUP and one translation was agreed which was back-translated and pre-tested on five pregnant women using cognitive interviews. The measure was field tested with pregnant women who were recruited at antenatal clinics and data were analysed using classical test theory and hypothesis testing.Results: 125 women aged 15-43 (median 23), with parities of 1-8 (median 2) completed the Chichewa LMUP. There were no missing data. The full range of LMUP scores was captured. In terms of reliability, the scale was internally consistent (Cronbach's alpha = 0.78) and test-retest data from 70 women showed good stability (weighted Kappa 0.80). In terms of validity, hypothesis testing confirmed that unmarried women (p = 0.003), women who had four or more children alive (p = 0.0051) and women who were below 20 or over 29 (p = 0.0115) were all more likely to have unintended pregnancies. Principal component analysis showed that five of the six items loaded onto one factor, with a further item borderline. A sensitivity analysis to assess the effect of the removal of the weakest item of the scale showed slightly improved performance but as the LMUP was not significantly adversely affected by its inclusion we recommend retaining the six-item score.Conclusion: The Chichewa LMUP is a valid and reliable measure of pregnancy intention in Malawi and can now be used in research and/or surveillance. This is the first validation of this tool in a low-income country, helping to demonstrate that the concept of pregnancy planning is applicable in such a setting. Use of the Chichewa LMUP can enhance our understanding of pregnancy intention in Malawi, giving insight into the family planning services that are required to better meet women's needs and save lives. © 2013 Hall et al.; licensee BioMed Central Ltd.Dr Hall’s Wellcome Trust Research Training Fellowship, grant number 097268/Z/11/Z

Identification of the soft X-ray source WGA J1802.1+1804 with a new magnetic cataclysmic variable

We have discovered a bright (V~14.5) cataclysmic variable during observations of the soft X-ray sources in the list of Singh et al. The optical source, which is coincident with the X-ray position of WGA J1802.1+1804, shows all the characteristics of a magnetic AM Herculis-type system: circular polarization, He II strength greater than Hβ, multiple line components, and a consistent photometric, polarimetric, spectroscopic, and X-ray period of 113 minutes. The X-ray spectrum shows a dominant soft blackbody (kT=20-45 eV) and a weaker bremsstrahlung component (kT>1 keV), while the circular polarization is relatively low (4% in the red)

Exploiting High-Throughput Cell Line Drug Screening Studies to Identify Candidate Therapeutic Agents in Head and Neck Cancer

BACKGROUND: There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity. Recent advances in high-throughput drug screening techniques and next-generation sequencing have identified new therapeutic targets in other cancer types, but an HNSCC-specific study has not yet been carried out. We have exploited data from two large-scale cell line projects to clearly describe the mutational and copy number status of HNSCC cell lines and identify candidate drugs with elevated efficacy in HNSCC. METHODS: The genetic landscape of 42 HNSCC cell lines including mutational and copy number data from studies by Garnett et al., and Barretina et al., were analyzed. Data from Garnett et al. was interrogated for relationships between HNSCC cells versus the entire cell line pool using one- and two-way analyses of variance (ANOVAs). As only seven HNSCC cell lines were tested with drugs by Barretina et al., a similar analysis was not carried out. RESULTS: Recurrent mutations in human papillomavirus (HPV)-negative patient tumors were confirmed in HNSCC cell lines, however additional, recurrent, cell line-specific mutations were identified. Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC50 values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines. Furthermore, the PI3K inhibitor AZD6482 demonstrated significantly higher activity (as measured by the IC50) in HNSCC cell lines harbouring PIK3CA mutations versus those that did not. CONCLUSION: HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type