Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the ...artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P <10(-3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio OR, 17.5; 95% confidence interval CI, 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.).
How noncoding DNA determines gene expression in different cell types is a major unsolved problem, and critical downstream applications in human genetics depend on improved solutions. Here, we report ...substantially improved gene expression prediction accuracy from DNA sequences through the use of a deep learning architecture, called Enformer, that is able to integrate information from long-range interactions (up to 100 kb away) in the genome. This improvement yielded more accurate variant effect predictions on gene expression for both natural genetic variants and saturation mutagenesis measured by massively parallel reporter assays. Furthermore, Enformer learned to predict enhancer-promoter interactions directly from the DNA sequence competitively with methods that take direct experimental data as input. We expect that these advances will enable more effective fine-mapping of human disease associations and provide a framework to interpret cis-regulatory evolution.
Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory ...cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic retinopathy. Retinoic acid-related orphan receptor gammaT (RORγt) is a ligand-dependent transcription factor that mediates IL-17A production. However, the role of RORγt in diabetes-mediated retinal inflammation and capillary degeneration, as well as its potential therapeutic attributes for diabetic retinopathy has not yet been determined. In the current study, we examined retinal inflammation and vascular pathology in streptozotocin-induced diabetic mice. We found RORγt expressing cells in the retinal vasculature of diabetic mice. Further, diabetes-mediated retinal inflammation, oxidative stress, and retinal endothelial cell death were all significantly lower in RORγt
mice. Finally, when a RORγt small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for RORγt in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease.
IL-17A Enhances Retinal Neovascularization Taylor, Brooklyn E; Lee, Chieh A; Zapadka, Thomas E ...
International journal of molecular sciences,
01/2023, Letnik:
24, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages ...of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.
To predict hospital admission at the time of ED triage using patient history in addition to information collected at triage.
This retrospective study included all adult ED visits between March 2014 ...and July 2017 from one academic and two community emergency rooms that resulted in either admission or discharge. A total of 972 variables were extracted per patient visit. Samples were randomly partitioned into training (80%), validation (10%), and test (10%) sets. We trained a series of nine binary classifiers using logistic regression (LR), gradient boosting (XGBoost), and deep neural networks (DNN) on three dataset types: one using only triage information, one using only patient history, and one using the full set of variables. Next, we tested the potential benefit of additional training samples by training models on increasing fractions of our data. Lastly, variables of importance were identified using information gain as a metric to create a low-dimensional model.
A total of 560,486 patient visits were included in the study, with an overall admission risk of 29.7%. Models trained on triage information yielded a test AUC of 0.87 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.88) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on patient history yielded an AUC of 0.86 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.87) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on the full set of variables yielded an AUC of 0.91 for LR (95% CI 0.91-0.91), 0.92 for XGBoost (95% CI 0.92-0.93) and 0.92 for DNN (95% CI 0.92-0.92). All algorithms reached maximum performance at 50% of the training set or less. A low-dimensional XGBoost model built on ESI level, outpatient medication counts, demographics, and hospital usage statistics yielded an AUC of 0.91 (95% CI 0.91-0.91).
Machine learning can robustly predict hospital admission using triage information and patient history. The addition of historical information improves predictive performance significantly compared to using triage information alone, highlighting the need to incorporate these variables into prediction models.
Degradable polymers are used widely in tissue engineering and regenerative medicine. Maturing capabilities in additive manufacturing coupled with advances in orthogonal chemical functionalization ...methodologies have enabled a rapid evolution of defect-specific form factors and strategies for designing and creating bioactive scaffolds. However, these defect-specific scaffolds, especially when utilizing degradable polymers as the base material, present processing challenges that are distinct and unique from other classes of materials. The goal of this review is to provide a guide for the fabrication of biodegradable polymer-based scaffolds that includes the complete pathway starting from selecting materials, choosing the correct fabrication method, and considering the requirements for tissue specific applications of the scaffold.
To assess the number of individuals visually impaired or blind due to glaucoma and to examine regional differences and temporal changes in this parameter for the period from 1990 to 2012.
As part of ...the Global Burden of Diseases (GBD) Study 2010, we performed a systematic literature review for the period from 1980 to 2012. We primarily identified 14,908 relevant manuscripts, out of which 243 high-quality, population-based studies remained after review by an expert panel that involved application of selection criteria that dwelt on population representativeness and clarity of visual acuity methods used. Sixty-six specified the proportion attributable to glaucoma. The software tool DisMod-MR (Disease Modeling-Metaregression) of the GBD was used to calculate fraction of vision impairment due to glaucoma.
In 2010, 2.1 million (95% Uncertainty Interval (UI):1.9,2.6) people were blind, and 4.2 (95% UI:3.7,5.8) million were visually impaired due to glaucoma. Glaucoma caused worldwide 6.6% (95% UI:5.9,7.9) of all blindness in 2010 and 2.2% (95% UI:2.0,2.8) of all moderate and severe visual impairment (MSVI). These figures were lower in regions with younger populations (<5% in South Asia) than in high-income regions with relatively old populations (>10%). From 1990 to 2010, the number of blind or visually impaired due to glaucoma increased by 0.8 million (95%UI:0.7, 1.1) or 62% and by 2.3 million (95%UI:2.1,3.5) or 83%, respectively. Percentage of global blindness caused by glaucoma increased between 1990 and 2010 from 4.4% (4.0,5.1) to 6.6%. Age-standardized prevalence of glaucoma related blindness and MSVI did not differ markedly between world regions nor between women.
By 2010, one out of 15 blind people was blind due to glaucoma, and one of 45 visually impaired people was visually impaired, highlighting the increasing global burden of glaucoma.
Summary Background Data on causes of vision impairment and blindness are important for development of public health policies, but comprehensive analysis of change in prevalence over time is lacking. ...Methods We did a systematic analysis of published and unpublished data on the causes of blindness (visual acuity in the better eye less than 3/60) and moderate and severe vision impairment (MSVI visual acuity in the better eye less than 6/18 but at least 3/60) from 1980 to 2012. We estimated the proportions of overall vision impairment attributable to cataract, glaucoma, macular degeneration, diabetic retinopathy, trachoma, and uncorrected refractive error in 1990–2010 by age, geographical region, and year. Findings In 2010, 65% (95% uncertainty interval UI 61–68) of 32·4 million blind people and 76% (73–79) of 191 million people with MSVI worldwide had a preventable or treatable cause, compared with 68% (95% UI 65–70) of 31·8 million and 80% (78–83) of 172 million in 1990. Leading causes worldwide in 1990 and 2010 for blindness were cataract (39% and 33%, respectively), uncorrected refractive error (20% and 21%), and macular degeneration (5% and 7%), and for MSVI were uncorrected refractive error (51% and 53%), cataract (26% and 18%), and macular degeneration (2% and 3%). Causes of blindness varied substantially by region. Worldwide and in all regions more women than men were blind or had MSVI due to cataract and macular degeneration. Interpretation The differences and temporal changes we found in causes of blindness and MSVI have implications for planning and resource allocation in eye care. Funding Bill & Melinda Gates Foundation, Fight for Sight, Fred Hollows Foundation, and Brien Holden Vision Institute.
Extended BMS algebra of celestial CFT Fotopoulos, Angelos; Stieberger, Stephan; Taylor, Tomasz R. ...
The journal of high energy physics,
03/2020, Letnik:
2020, Številka:
3
Journal Article
Recenzirano
Odprti dostop
A
bstract
We elaborate on the proposal of flat holography in which four-dimensional physics is encoded in two-dimensional celestial conformal field theory (CCFT). The symmetry underlying CCFT is the ...extended BMS symmetry of (asymptotically) flat space time. We use soft and collinear theorems of Einstein-Yang-Mills theory to derive the OPEs of BMS field operators generating superrotations and supertranslations. The energy momentum tensor, given by a shadow transform of a soft graviton operator, implements superrotations in the Virasoro subalgebra of 𝔟𝔪𝔰
4
. Supertranslations can be obtained from a single translation generator along the light-cone direction by commuting it with the energy-momentum tensor. This operator also originates from a soft graviton and generates a flow of conformal dimensions. All supertranslations can be assembled into a single primary conformal field operator on celestial sphere.
Multivalent ion batteries (MVIBs) provide an inexpensive and energy-dense alternative to Li-ion batteries when portability of the battery is not of primary concern. However, it is difficult to find ...cathode materials that provide optimal battery characteristics such as energy density, adequate charge/discharge rates, and cyclability when paired with a multivalent ion. To address this, we investigate six MnO2 polymorphs as cathodes for MVIBs using density functional theory calculations. We find voltages as high as 3.7, 2.4, 2.7, 1.8, and 1.0 V for Li, Mg, Ca, Al, and Zn, respectively, and calculate the volume change due to intercalation. We then focus specifically on Ca and compute the energy barriers which are associated with the diffusion of the ion throughout the materials. Our findings show that the α-phase displays the most rapid diffusion kinetics for a Ca ion, with a diffusion barrier as low as 190 meV. We then investigate the potential for the five polymorphs exhibiting the highest voltage to intercalate additional atoms and demonstrate that it is energetically favorable for each to accept at least one additional Ca ion; furthermore, two of the phases can accept more than two Ca ions. However, in each case, there is also a corresponding drop in the voltage as further atoms are intercalated. We also utilize a crystal-chemistry approach to detail the structural evolution of each phase by computing the bond valence sum and effective coordination of the Mn4+ ions upon intercalation of increasing numbers of Ca ions. Finally, by computing the electronic density of states, Bader charges, and real space charge density, we describe how the additional electrons from the Ca ions are distributed throughout the unit cell. These insights provide guidance in selecting a MnO2 polymorph with the traits necessary for the realization of MVIBs.
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