Something in it for the underdog: the playwriting of Joan Ure

No abstract available

"Two kingdoms...compassed with one Sea": reconstructing kingdoms and reclaiming histories in David Greig's Dunsinane

No abstract available

Lower Extremity Ulcers in Systemic Sclerosis: Features and Response to Therapy

Nondigital lower extremity ulcers are a difficult to treat complication of scleroderma, and a significant cause of morbidity. The purpose of this study was to evaluate the prevalence of nondigital lower extremity ulcers in scleroderma and describe the associations with autoantibodies and genetic prothrombotic states. A cohort of 249 consecutive scleroderma patients seen in the Georgetown University Hosptial Division of Rheumatology was evaluated, 10 of whom had active ulcers, giving a prevalence of 4.0%. Patients with diffuse scleroderma had shorter disease duration at the time of ulcer development (mean 4.05 years ± 0.05) compared to those with limited disease (mean 22.83 years ± 5.612, P value .0078). Ulcers were bilateral in 70%. In the 10 patients with ulcers, antiphospholipid antibodies were positive in 50%, and genetic prothrombotic screen was positive in 70% which is higher than expected based on prevalence reports from the general scleroderma population. Of patients with biopsy specimens available (n = 5), fibrin occlusive vasculopathy was seen in 100%, and all of these patients had either positive antiphospholipid antibody screen, or positive genetic prothrombotic profile. We recommend screening scleroderma patients with lower extremity ulcers for the presence of anti-phospholipid antibodies and genetic prothrombotic states

Covalent bond shortening and distortion induced by pressurization of thorium, uranium, and neptunium tetrakis aryloxides

Covalency involving the 5f orbitals is regularly invoked to explain the reactivity, structure and spectroscopic properties of the actinides, but the ionic versus covalent nature of metal-ligand bonding in actinide complexes remains controversial. The tetrakis 2,6-di-tert-butylphenoxide complexes of Th, U and Np form an isostructural series of crystal structures containing approximately tetrahedral MO(4) cores. We show that up to 3 GPa the Th and U crystal structures show negative linear compressibility as the OMO angles distort. At 3 GPa the angles snap back to their original values, reverting to a tetrahedral geometry with an abrupt shortening of the M-O distances by up to 0.1 Å. The Np complex shows similar but smaller effects, transforming above 2.4 GPa. Electronic structure calculations associate the M-O bond shortening with a change in covalency resulting from increased contributions to the M-O bonding by the metal 6d and 5f orbitals, the combination promoting MO(4) flexibility at little cost in energy

Asthma phenotyping in primary care : applying the International Severe Asthma Registry eosinophil phenotype algorithm across all asthma severities.

Funding: The OPCRD is established and maintained by Optimum Patient Care (OPC) Ltd. This study was funded by AstraZeneca and conducted collaboratively with the OPRI Pte Ltd and OPC Global Ltd. Acknowledgements We thank James Zangrilli, MD, and the entire ISAR Steering Committee for their valued contribution to the design of the study and interpretation of findingsPeer reviewedPublisher PD

Measuring disease-specific quality of life in rare populations: a practical approach to cross-cultural translation

<p>Abstract</p> <p>Background</p> <p>Disease-specific quality of life (QoL) measures have enhanced the capacity of outcome measures to evaluate subtle changes and differences between groups. However, when the specific disease is rare, the cohort of patients is small and international collaboration is often necessary to accomplish meaningful research. As many of the QoL measures have been developed in North American English, they require translation to ensure their usefulness in a multi-cultural and/or international society. Published guidelines provide formal methods to achieve cross-culturally comparable versions of a QoL tool. However, these guidelines describe a rigorous process that is not always feasible, particularly in rare disease groups. The objective of this manuscript is to describe the process that was developed to achieve accurate cross-cultural translations of a disease-specific QoL measure, to overcome the challenges of a small sample size, i.e. children with a rare disorder.</p> <p>Procedure</p> <p>A measurement study was conducted in the United Kingdom (UK), France, Germany and Uruguay, during which the validated measure was translated into the languages of the respective countries.</p> <p>Results</p> <p>This is a report of a modified, child-centric, cross-cultural translation and adaptation process in which culturally appropriate and methodologically valid translations of a disease-specific QoL measure, the Kids' ITP Tools (KIT), were performed in children with immune thrombocytopenic purpura (ITP). The KIT was translated from North American English into UK English, French, German, and Spanish.</p> <p>Conclusion</p> <p>This study was a successful international collaboration. The modified process through which culturally appropriate and methodologically valid translations of QoL measures may be achieved in a pediatric population with a relatively rare disorder is reported.</p

Lower pneumonia risk in COPD patients initiating fixed dose combination (FDC) inhaler comprising extrafine beclometasone dipropionate versus fluticasone

Grant support: This study was funded by Chiesi Farmaceutici S.p.A. David Price has grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; is a peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline.Peer reviewe

Development of the Advancing the Patient Experience in COPD Registry:A Modified Delphi Study

Background: Chronic obstructive pulmonary disease (COPD) is commonly managed by family physicians, but little is known about specifics of management and how this may be improved. The Advancing the Patient Experience in COPD (APEX COPD) registry will be the first U.S. primary care, health system-based registry following patients diagnosed with COPD longitudinally, using a standardized set of variables to investigate how patients are managed in real life and assess outcomes of various management strategies.Objective: Gaining expert consensus on a standardized list of variables to capture in the APEX COPD registry.Methods: A modified, Delphi process was used to reach consensus on which data to collect in the registry from electronic health records (EHRs), patient-reported information (PRI) and patient-reported outcomes (PRO), and by physicians during subsequent office visits. The Delphi panel comprised 14 primary care and specialty COPD experts from the United States and internationally. The process consisted of 3 iterative rounds. Responses were collected electronically.Results: Of the initial 195 variables considered, consensus was reached to include up to 115 EHR variables, 34 PRI/PRO variables and 5 office-visit variables in the APEX COPD registry. These should include information on symptom burden, diagnosis, COPD exacerbations, lung function, quality of life, comorbidities, smoking status/history, treatment specifics (including side effects), inhaler management, and patient education/self-management.Conclusion: COPD experts agreed upon the core variables to collect from EHR data and from patients to populate the APEX COPD registry. Data will eventually be integrated, standardized and stored in the APEX COPD database and used for approved COPD-related research.</p

Development of the Advancing the Patient Experience (APEX) in COPD Registry : A Modified Delphi Study

Funding statement: APEX COPD is conducted by Optimum Patient Care (OPC) Global Limited, and co-funded by OPC Global and Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and/or formatting assistance was provided by Ms. Audrey Ang of the Observational and Pragmatic Research Institute, Singapore, and Dr. Lisa Buttle of Medscript Ltd, Ireland, which was funded by BIPI. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Acknowledgments The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). We thank Dr. Alvaro Aranda (Hospital Auxilio Mutuo, San Juan, Puerto Rico) for his scientific and clinical contributions during the drafting of this manuscript. We also thank Ms. Audrey Ang for editorial assistance, Ms. Bronte Sawyer for project coordination, and Dr. Lisa Buttle for assistance with drafting the article. Dr. Ruth B. Murray is acknowledged for her substantial contribution to the interpretation, summarization and presentation of data in this article and significant intellectual input to the manuscript. She has provided her final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Dr. Ruth B. Murray is the founder and director of Medscript Ltd., a company that provided writing and editorial support for APEX COPD publications.Peer reviewedPostprin

Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure

BackgroundVariation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia (SCZ) and bipolar disorder (BP). Evidence suggests that ZNF804A is a regulator of gene transcription and is present in nuclear and extranuclear compartments. However, a detailed examination of ZNF804A distribution and its neuronal functions has yet to be performed.MethodsThe localization of ZNF804A protein was examined in neurons derived from human neural progenitor cells (hNPCs), human induced pluripotent stem cells (hiPSCs) or in primary rat cortical neurons. Additionally, siRNA-mediated knockdown of ZNF804A was conducted to determine its role in neurite formation, maintenance of dendritic spine morphology and responses to activity-dependent stimulations.ResultsEndogenous ZNF804A protein localized to somato-dendritic compartments and co-localized with the putative synaptic markers in young neurons derived from hNPCs and hiPSCs. In mature rat neurons, Zfp804A, the homolog of ZNF804A, was present in a subset of dendritic spines and co-localized with synaptic proteins in specific nanodomains, as determined by superresolution microscopy. Interestingly, knockdown of ZNF804A attenuated neurite outgrowth in young neurons, an effect potentially mediated by reduced neuroligin-4 (NLGN4) expression. Furthermore, knockdown of ZNF804A in mature neurons resulted in the loss of dendritic spine density, and impaired responses to activity-dependent stimulation.ConclusionsThese data reveal a novel subcellular distribution for ZNF804A within somato-dendritic compartments and a nanoscopic organisation at excitatory synapses. Moreover, our results suggest that ZNF804A plays an active role in neurite formation, maintenance of dendritic spines and activity-dependent structural plasticity