Successful large gene augmentation of USH2A with non-viral episomal vectors

USH2A mutations are a common cause of autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, for which there are currently no approved treatments. Gene augmentation is a valuable therapeutic strategy for treating many inherited retinal diseases; however, conventional adeno-associated virus (AAV) gene therapy cannot accommodate cDNAs exceeding 4.7 kb, such as the 15.6-kb-long USH2A coding sequence. In the present study, we adopted an alternative strategy to successfully generate scaffold/matrix attachment region (S/MAR) DNA plasmid vectors containing the full-length human USH2A coding sequence, a GFP reporter gene, and a ubiquitous promoter (CMV or CAG), reaching a size of approximately 23 kb. We assessed the vectors in transfected HEK293 cells and USH2A patient-derived dermal fibroblasts in addition to ush2au507 zebrafish microinjected with the vector at the one-cell stage. pS/MAR-USH2A vectors drove persistent transgene expression in patient fibroblasts with restoration of usherin. Twelve months of GFP expression was detected in the photoreceptor cells, with rescue of Usher 2 complex localization in the photoreceptors of ush2au507 zebrafish retinas injected with pS/MAR-USH2A. To our knowledge, this is the first reported vector that can be used to express full-length usherin with functional rescue. S/MAR DNA vectors have shown promise as a novel non-viral retinal gene therapy, warranting further translational development

Optimizing dual energy cone beam CT protocols for preclinical imaging and radiation research

Objective: The aim of this work was to investigate whether quantitative dual-energy CT (DECT) imaging is feasible for small animal irradiators with an integrated cone-beam CT (CBCT) system. Methods: The optimal imaging protocols were determined by analyzing different energy combinations and dose levels. The influence of beam hardening effects and the performance of a beam hardening correction (BHC) were investigated. In addition, two systems from different manufacturers were compared in terms of errors in the extracted effective atomic numbers (Z(eff)) and relative electron densities (rho(e)) for phantom inserts with known elemental compositions and relative electron densities. Results: The optimal energy combination was determined to be 50 and 90kVp. For this combination, Z(eff) and r rho(e) can be extracted with a mean error of 0.11 and 0.010, respectively, at a dose level of 60cGy. Conclusion: Quantitative DECT imaging is feasible for small animal irradiators with an integrated CBCT system. To obtain the best results, optimizing the imaging protocols is required. Well-separated X-ray spectra and a sufficient dose level should be used to minimize the error and noise for Z(eff) and rho(e). When no BHC is applied in the image reconstruction, the size of the calibration phantom should match the size of the imaged object to limit the influence of beam hardening effects. No significant differences in Z(eff) and rho(e) errors are observed between the two systems from different manufacturers. Advances in knowledge: This is the first study that investigates quantitative DECT imaging for small animal irradiators with an integrated CBCT system

Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

Peer reviewe

2019 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations : summary from the basic life support; advanced life support; pediatric life support; neonatal life support; education, implementation, and teams; and first aid task forces

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research

Precise measurement of the W-boson mass with the CDF II detector

We have measured the W-boson mass MW using data corresponding to 2.2/fb of integrated luminosity collected in proton-antiproton collisions at 1.96 TeV with the CDF II detector at the Fermilab Tevatron collider. Samples consisting of 470126 W->enu candidates and 624708 W->munu candidates yield the measurement MW = 80387 +- 12 (stat) +- 15 (syst) = 80387 +- 19 MeV. This is the most precise measurement of the W-boson mass to date and significantly exceeds the precision of all previous measurements combined

Normative resistance to responsibility to protect in times of emerging multipolarity: the cases of Brazil and Russia

This article assesses the normative resistance to Responsibility to Protect adopted by Brazil and Russia against the backdrop of their international identities and self-assigned roles in a changing global order. Drawing upon the framework of Bloomsfield's norm dynamics role spectrum, it argues that while the ambiguous Russian role regarding this principle represents an example of 'norm antipreneurship', particularities of Brazil's resistance are better grasped by a new category left unaccounted for by this model, which this study portrays as 'contesting entrepreneur'.- (undefined

Shock and stabilisation following long-term drought in tropical forest from 15 years of litterfall dynamics

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.1.Litterfall dynamics in tropical forests are a good indicator of overall tropical forest function, indicative of carbon invested in both photosynthesising tissues and reproductive organs such as flowers and fruits. These dynamics are sensitive to changes in climate, such as drought, but little is known about the long-term responses of tropical forest litterfall dynamics to extended drought stress. 2.We present a 15-year dataset of litterfall (leaf, flower and fruit, and twigs) from the world's only long-running drought experiment in tropical forest. This data set comprises one of the longest published litterfall time-series in natural forest, which allows the long-term effects of drought on forest reproduction and canopy investment to be explored. 3.Over the first four years of the experiment, the experimental soil moisture deficit created only a small decline in total litterfall and leaf fall (12% and 13% respectively), but a very strong initial decline in reproductive litterfall (flowers and fruits) of 54%. This loss of flowering and fruiting was accompanied by a de-coupling of all litterfall patterns from seasonal climate variables. However, following >10 years of the experimental drought, flower and fruiting re-stabilised at levels greater than in the control plot, despite high tree mortality in the drought plot. Litterfall relationships with atmospheric drivers were re-established alongside a strong new apparent trade-off between litterfall and tree growth. 4.Synthesis: we demonstrate that this tropical forest went through an initial shock response during the first four years of intense drought, where reproductive effort was arrested and seasonal litterfall patterns were lost. However, following >10 years of experimental drought this system appears to be re-stabilising at a new functional state where reproduction is substantially elevated on a per tree basis; and there is a new strong trade-off between investment in canopy production and wood production.This work is a product of UK NERC grant NE/J011002/1 to PM and MM, UK NERC independent fellowship grant NE/N014022/1 to LR, CNPQ grant 457914/2013-0/MCTI/CNPq/FNDCT/LBA/ESECAFLOR to ACLD, an ARC grant DP17010409to PM. It was previously supported by NERC NER/A/S/2002/00487, NERC GR3/11706, EU FP5-Carbonsink and EU FP7-Amazalert to PM and a grant from the Gordon and Betty Moore Foundation to Y

A systematic evaluation of payback of publicly funded health and health services research in Hong Kong

<p>Abstract</p> <p>Background</p> <p>The Health and Health Services Research Fund (HHSRF) is dedicated to support research related to all aspects of health and health services in Hong Kong. We evaluated the fund's outcomes and explored factors associated with the translation of research findings to changes in health policy and provider behaviour.</p> <p>Methods</p> <p>A locally suitable questionnaire was developed based on the "payback" evaluation framework and was sent to principal investigators of the completed research projects supported by the fund since 1993. Research "payback" in six outcome areas was surveyed, namely knowledge production, use of research in the research system, use of research project findings in health system policy/decision making, application of the research findings through changed behaviour, factors influencing the utilization of research, and health/health service/economic benefits.</p> <p>Results</p> <p>Principal investigators of 178 of 205 (87%) completed research projects returned the questionnaire. Investigators reported research publications in 86.5% (mean = 5.4 publications per project), career advancement 34.3%, acquisition of higher qualifications 38.2%, use of results in policy making 35.4%, changed behaviour in light of findings 49.4%, evidence of health service benefit 42.1% and generated subsequent research in 44.9% of the projects. Payback outcomes were positively associated with the amount of funding awarded. Multivariate analysis found participation of investigators in policy committees and liaison with potential users were significantly associated with reported health service benefit (odds ratio [OR]_{participation}= 2.86, 95% confidence interval [CI] 1.28–6.40; OR_liaison= 2.03, 95% CI 1.05–3.91), policy and decision-making (OR_{participation}= 10.53, 95% CI 4.13–26.81; OR_liaison= 2.52, 95% CI 1.20–5.28), and change in behavior (OR_{participation}= 3.67, 95% CI 1.53–8.81).</p> <p>Conclusion</p> <p>The HHSRF has produced substantial outcomes and compared favourably with similar health research funds in other developed economies. Further studies are needed to better understand the factors and pathways associated with the translation of research findings into practice.</p

Essential data dimensions for prospective international data collection in older age bipolar disorder (OABD):Recommendations from the GAGE-BD group

Background: By 2030, over 50% of individuals living with bipolar disorder (BD) are expected to be aged ≥50 years. However, older age bipolar disorder (OABD) remains understudied. There are limited large-scale prospectively collected data organized in key dimensions capable of addressing several fundamental questions about BD affecting this subgroup of patients.Methods: We developed initial recommendations for the essential dimensions for OABD data collection, based on (1) a systematic review of measures used in OABD studies, (2) a Delphi consensus of international OABD experts, (3) experience with harmonizing OABD data in the Global Aging &amp; Geriatric Experiments in Bipolar Disorder Database (GAGE-BD, n ≥ 4500 participants), and (4) critical feedback from 34 global experts in geriatric mental health.Results: We identified 15 key dimensions and variables within each that are relevant for the investigation of OABD: (1) demographics, (2) core symptoms of depression and (3) mania, (4) cognition screening and subjective cognitive function, (5) elements for BD diagnosis, (6) descriptors of course of illness, (7) treatment, (8) suicidality, (9) current medication, (10) psychiatric comorbidity, (11) psychotic symptoms, (12) general medical comorbidities, (13) functioning, (14) family history, and (15) other. We also recommend particular instruments for capturing some of the dimensions and variables.Conclusion: The essential data dimensions we present should be of use to guide future international data collection in OABD and clinical practice. In the longer term, we aim to establish a prospective consortium using this core set of dimensions and associated variables to answer research questions relevant to OABD.</p